Efficient synthesis of the pharmacophore of the highly potent antitumor antibiotic CC-1065

Article abstract of DOI:10.1002/(SICI)1521-3765(19980807)4:8<1554::AID-CHEM1554>3.0.CO;2-J

The pharmacophore CPI (3) of the potent antitumor antibiotic CC-1065 (1) was synthesized in a very short reaction sequence of 11 steps with an overall yield of 23 %. The key steps are two consecutive cyclizations mediated by organotransition metal complexes, which form first the pyrroline and then the pyrrole ring in 3. Thus, halogen metal exchange of the N,N'-bisallylbromobenzene with tBuLi and subsequent reaction with Cp₂ZrMeCl gave 11 as a single product in 60 % yield after quenching with two equivalents of iodine. Transformation of the iodomethyl group in 11 into an acetoxymethyl group, followed by Heck reaction, isomerization, and reductive cleavage, provided the pyrroloindoline system 4, which was converted into 3.

Full text of DOI:10.1002/(SICI)1521-3765(19980807)4:8<1554::AID-CHEM1554>3.0.CO;2-J

FULL PAPER
Efficient Synthesis of the Pharmacophore of the Highly Potent Antitumor
Antibiotic CC-1065
Lutz F. Tietze,* Wilm Buhr, Jan Looft, and Thomas Grote
Abstract: The pharmacophore CPI (3) of the potent antitumor antibiotic CC-1065
(1) was synthesized in a very short reaction sequence of 11 steps with an overall yield
of 23%. The key steps are two consecutive cyclizations mediated by organotransition
metal complexes, which form first the pyrroline and then the pyrrole ring in 3. Thus,
halogen metal exchange of the N,N'-bisallylbromobenzene with tBuLi and subsequent
reaction with Cp2ZrMeCl gave 11 as a single product in 60% yield after quenching
with two equivalents of iodine. Transformation of the iodomethyl group in 11 into an
acetoxymethyl group, followed by Heck reaction, isomerization, and reductive
cleavage, provided the pyrroloindoline system 4, which was converted into 3.
Keywords: antibiotics
agents ´ cyclizations ´ Heck reaction
´ zirconium
´ antitumor
Introduction
units are identical and have a strong influence on the binding
specification[2] and the biological potency,[3] but are less toxic
themselves. However, the selectivity of CC-1065 and its
analogues in the differentiation between normal and malig-
nant cells is low, and furthermore, CC-1065 itself has a
delayed lethal liver toxicity. An approach to improve the
selectivity of CC-1065 and its analogues is the exploitation of
genetic and phenotypic differences of cancer and normal cells.
Thus, recently we developed nontoxic prodrugs of CC-1065[4]
that can be activated using conjugates of enzymes and
antibodies[5] which bind to tumor-associated antigens.
Cell investigations have shown that CC-1065 alkylates
DNA reversibly with a high sequence selectivity at AT-rich
regions of the minor groove sites [5'd(A/GNTTA)-3' and
5'd(AAAAA)-3'].[6] Because it is such a highly potent
pharmacophore, there is a great interest in the preparation
of the CPI unit. Thus, several syntheses of CPI have been
published so far.[7]
The antibiotic CC-1065 (1), first isolated from Streptomyces
zelensis in 1978 at the Upjohn Company, is one of the most
potent antitumor agents known.[1] It consists of three pyrro-
lo[3,2-e]dihydroindole moieties, of which the A unit 2, called
CPI, is the pharmacophore. It contains an unusual spirocy-
clopropyl group, which is able to alkylate DNA. The B and C
Here we describe an efficient and short synthesis of the
seco-CPI derivative 4, which is used for the preparation of
prodrugs of CC-1065,[4] and the N-(benzenesulfonyl)-CPI (3)
from commercially available 2-methoxy-4-nitroaniline (8)
based on two successive organotransition metal complex-
controlled cyclizations.[8] This allows the consecutive forma-
tion of the pyrroline and the pyrrole ring of the CPI and the
seco-CPI systems in 4 steps with 51% yield based on 6.
[*] Prof. Dr. Dr. h.c. L. F. Tietze, Dr. W. Buhr, Dipl.-Chem. J. Looft,
Dr. T. Grote
Institut für Organische Chemie
Results and Discussion
der Georg August-Universität Göttingen
Tammannstrasse 2, D-37077 Göttingen (Germany)
Fax: (‡49)551-399476
The retrosynthetic analysis of 3 (Scheme 1) first leads to 4 by
breaking the spirocyclopropane moiety. The transformation
E-mail: ltietze@gwdg.de
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1554±1560
of 4 into 3 had already been known and can easily be
performed using azodicarboxylate.[7e] Cleavage of the pyrrole
ring in 4 gives compound 5, which is clearly a good substrate
for a Heck reaction.[7d, 7f, 9] Cleavage of the second hetero-
cyclic ring would yield the benzene derivative 6 calling for a
reaction which not only forms the pyrroline moiety by C ± C-
bond formation but also introduces a functionalized side chain
and an iodo atom at the benzene ring necessary for the Heck
reaction. Such a reaction can be performed using Cp2ZrMeCl
and quenching with iodine.[10] The substrate 6 is easily
accessible from the diamine 7 by formation of the disulfon-
amide, bromination, and bis-allylation, and 7 can be obtained
from 8 by reduction.
Scheme 2. Synthesis of compound 6. Reaction conditions: a) PtO2/H2,
dioxane, 18 h, 3 bar, quant.; b) PhSO2Cl, pyridine, 3 h, 808C, 77%; c) NBS,
THF, 78 !208C, 95%; d) NaH, THF, 1 h, 208C; allyl bromide, nBu4NI,
5 h, 508C, 95%.
iodine.[12] Thus, addition of 2 equiv of tBuLi to a suspension of
6 and zirconocenemethylchloride[13] in tetrahydrofuran at
788C afforded at first the phenyllithium derivative 13 by
halogen ± metal exchange; transmetallation then led to the
zirconium complex 14, which loses methane to give (presum-
ably) the higly unstable 16-electron zirconacyclopropene
complex 15 (Scheme 3). Stabilization by a regioselective
insertion into the N2-allyl moiety yielded the zirconacyclo-
pentene complex 16, which reacted with two equivalents of
iodine to yield the desired indoline derivative 11. It should be
pointed out that the iodine used must be anhydrous otherwise
small amounts of 12 will be formed. If only one equivalent of
iodine is added, followed by workup with aqueous hydro-
chloric acid, 12 is the final product. This clearly shows that the
iodine inserts into the zirconium ± aryl bond first. This
observed selectivity prompted us to investigate the possibility
of further differentiating between the zirconium ± aryl and
zirconium ± alkyl bonds.[14] However, all attempts to introduce
an iodine atom at the aryl moiety and a different halogen
atom at the side chain in compound 16 using two different
halogen-donating agents like iodine and interhalogens, N-
halogenoimides, bromo-Meldrumꢁs acid, or bromotrichloro-
methane failed.
An unexpected result in the formation of 11 was the high
regioselectivity of the insertion of the zirconacarbene moiety
into the allyl group at N2. For the explanation of this
selectivity and to extend the application to other substrates,
the diamide 20 was prepared with a bromo substituent meta to
the methoxy group. Diamide 20 was obtained from 8 in four
steps with an overall yield of 61% (Scheme 4). Bromination
of 8 with N-bromosuccinimide in tetrahydrofuran gave 17 in a
highly regioselective manner; 17 was then reduced with
hydrazine hydrate to afford 18. Without further purification
18 was immediately converted with benzenesulfonylchloride
to give the stable bis-sulfonamide 19. Double allylation of 19
with allyl bromide in tetrahydrofuran in the presence of
tetrabutylammonium iodide yielded the N,N'-bis-allylphenyl-
enediamine 20. Cyclization of 20 as described for 6 again
furnished exclusively the indoline 11.
Scheme 1. Retrosynthetic analysis of CPI.
Hydrogenation of 8 in dioxane with Pt at 3 bar afforded 7,
which was not purified due to its high sensitivity to oxidation,
but immediately converted with benzenesulfonyl chloride in
degassed pyridine to give the stable sulfonamide 9.[11]
Subsequently, bromination of 9 with N-bromosuccinimide in
tetrahydrofuran afforded 10 as the sole product (Scheme 2).
Regioisomeric brominated compounds were not detected
under these conditions. The following double allylation of 10
with allyl bromide in tetrahydrofuran in the presence of
tetrabutylammonium iodide gave the bis-allylphenylenedi-
amide 6 in an overall yield of 66% over the four steps. A great
advantage of this sequence is that all compounds except 7
could be purified by a simple crystallization.
Two conclusions can be drawn from this experiment: firstly,
the reaction has to proceed through 15 or the corresponding
benzyne complex. Secondly, the regioselectivity of the reac-
tion is exclusively controlled by the methoxy group and not by
The diamide 6 was then transformed into the indoline 11
with a iodomethyl group at C-3 and a iodo atom at C-4 by a
zirconocene-mediated cyclization followed by workup with
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L. F. Tietze et al.
FULL PAPER
the position of the bromine atom in the starting
material. We assume that the regioselectivity is ruled
by both steric hindrance and stereoelectronics. Thus,
a proper orientation of the allyl moiety at N1 is
disturbed by the methoxy group in the ortho position;
this causes an increase in activation energy of the
insertion step. On the other hand, calculations for 21
carried out by means of
SPARTAN[15] have provided
a structure of an extended
C ± Zr bond para to the me-
thoxy
group.
However,
Buchwald[10] has shown that
the reaction of p-bromome-
thoxybenzene with acetoni-
trile in the presence of
Cp2ZrMeCl provides the
two possible regioisomeric products as a 1:1 mixture.
This result calls for a steric explanation of the
regioselective formation of 11 from 6 and 20.
According to our retrosynthetic analysis the pyr-
role moiety in 4 should be formed by a Heck
reaction.[9] It was our hope that 11 could be used
directly in this transformation since iodoarenes are
more reactive than iodoalkanes; however, treatment
of 11 with Pd0 led to the formation of a methylpyrro-
loindole derivative. Therefore the iodomethyl group
in 11 was first transformed into an acetoxymethyl
group. In earlier work on the synthesis of CC-1065
analogues[8] we had shown that, by means of 1,8-
diazabicyclo[5.4.0]undec-7-ene,
the
iodomethyl
group can easily be transformed into an exocyclic
double bond, which on hydroboration becomes a
hydroxymethyl group. Since the yields for this two-
step transformation are not very high and a hydro-
boration is not possible due to the second double
bond in 11, we tried to replace the iodo atom by a
simple substitution with sodium acetate, cesium
Scheme 3. Mechanism of the zirconocene-induced cyclization. Reaction conditions:
a) tBuLi, Cp2ZrMeCl, THF, 19 h, 78 !208C; b) 2 equiv I2, CH2Cl2, 60% !11, or I2,
HCl, CH2Cl2, H2O !12.
acetate, tetrabutylammonium acetate and several other
nucleophiles. However, in all cases no substitution was
observed but rather elimination followed by partial isomer-
ization of the double bond to give the methylindole moiety. In
contrast, treatment of 11 with silver oxide on silica gel in
acetone and water at 208C for 24 h led to the hydroxymethyl
compound 22, which was acetylated with sodium acetate in
acetic anhydride to give the desired product 5 (Scheme 5).
Though the Heck reaction could also be performed with 22,
for the later cleavage of the aryl methyl ether with boron
tribromide the hydroxymethyl group had to be protected as
an acetate.
The Heck reaction of 5 gave the cyclized products 23 and 24
in a clean transformation (Scheme 5), in which the ratio of 23
and 24 could be controlled by means of different reaction
conditions (Table 1). With tetrakis(triphenylphosphane)pal-
ladium as catalyst and triethylamine as base in acetonitrile for
18 hours a 17:1 mixture of 23 to 24 was formed in 90% yield,
whereas treatment of 5 with catalytic amounts of palladium
acetate in the presence of silver carbonate[16] for three hours
gave 23 exclusively in 90% yield. It should be noted that the
Scheme 4. Synthesis of compound 11 from compound 20. Reaction
conditions: a) NBS, THF, 78 !208C, 96%; b)N2H4 ´ H2O, FeCl3, acti-
vated carbon, EtOH, reflux, 98%; c)PhSO2Cl, pyridine, 3 h, 808C, 81%;
d) NaH, THF, 1 h, 208C; allyl bromide, nBu4NI, 5 h, 508C, 80%; e) tBuLi,
Cp2ZrMeCl, 19 h, 78 !20C; 3 equiv I2, CH2Cl2, 37%.
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CC-1065 Pharmacophore
1554±1560
from 4. As already mentioned, the transforma-
tion of the seco-CPI 4 to the CPI derivative 3 is
known, and was performed by Mitsunobuꢁs
method[17]
(DEAD).
with
diethyl
azodicarboxylate
Conclusion
The synthesis of the pharmacologically active
CPI unit 3 described here was carried out in
11 steps with an overall yield of 23% starting
from commercially available 2-methoxy-4-nitro-
aniline 8. It is the shortest synthesis so far of CPI.
Scheme 5. Synthesis of the compounds 23 and 24 by Heck reaction of 5. Reaction
conditions: a) Ag2O, SiO2, acetone/H2O, 95%; b) Ac2O, NaOAc, 99%; c) Heck reaction,
90%.
concentration of 5 also has a great influence on the product
1
ratio. Palladium acetate at a low concentration (0.03 molL )
of 5 provided a 1.3:1 ratio of 23 and 24 and at higher
1
concentration (0.3 molL ) only 23 was formed.
Experimental Section
However, the selectivity of the Heck reaction is of little
importance since 23 had to be isomerized, which was achieved
with camphorsulfonic acid in dichloromethane at 208C to give
the protected seco-CPI unit 24 quantitatively.
General aspects: All reactions were performed in oven-dried glassware
under an atmosphere of argon unless otherwise stated. Melting points were
determined on a Mettler FP61 and are uncorrected. IR spectra were
recorded on a Bruker IFS25 FT-IR, and 1H NMR and 13C NMR spectra
with a Bruker AM-300 and a Varian VXR-200. Chemical shifts were
reported on the d scale relative to CDCl3 as internal standard. Mass spectra
were measured at 70 eV with a Varian MAT311A and the high-resolution
mass spectra with a Varian MAT731. TLC chromatography was performed
on precoated silica gel SIL G/UV254 plates (Machery Nagel). All products
were isolated by column chromatography on silica gel 32 ± 63 (0.063 ±
0.200 mm) (Machery Nagel) and silica gel 60 (0.040 ± 0.063 mm) (Merck).
The chiral compounds were obtained as racemic mixtures. The micro-
analyses were carried out by the Mikroanalytisches Labor of the Institute
of Organic Chemistry of the University of Göttingen.
Table 1. Heck reactions of 5.
Catalyst
Base
Solvent Conc
[molL
T [8C] t [h]
23 [%] 24 [%]
1
]
Pd(PPh3)4 Et3N
Pd(OAc)2 Ag2CO3 DMF
Pd(OAc)2 Ag2CO3 DMF
CH3CN 0.02
60 ± 70 18
85
90
50
5
±
40
0.3
0.03
20
20
3
3
N,N'-Dibenzenesulfonyl-2-methoxy-1,4-phenylenediamine (9): A solution
of 5-nitro-2-aminoanisole (8, 22.1 g, 0.13 mmol) in dioxane (170 mL) was
hydrogenated with PtO2 (0.20 g, 0.80 mmol) for 16 h at 3 atm of H2. The
mixture was filtered under argon and the solution evaporated in vacuo to
obtain the diamine 7 as a pink solid, which was immediately used for the
preparation of 9. Benzenesulfonyl chloride (34.0 mL, 0.26 mol) was added
slowly to a solution of 7 in dry degassed pyridine (300 mL) and the solution
stirred for 3 h at 808C. After concentration in vacuo to give a volume of
about 200 mL, ice-cold aqueous hydrochloric acid (500 mL, 5% HCl) was
added, the resulting black oil separated and crystallized from glacial acetic
Subsequently the protecting groups in 24 were removed.
First the methyl ether in 24 was cleaved to give the free phenol
25 by treatment with boron tribromide in dichloromethane at
108C for 3 h, and then the acetyl and the benzenesulfonyl
group at the indole nitrogen were removed with sodium bis(2-
methoxyethoxy)dihydroaluminate (Red-Al) kept at 08C for
3 h to provide the N-benzenesulfonyl-seco-CPI 4 in an overall
yield of 83% based on 24 (Scheme 6). It is also possible to
remove the acetate moiety first by solvolysis with potassium
carbonate in methanol to give 26, which is then treated with
Red-Al at 208C for 3 h. The two-step procedure has the
advantage that it avoids the formation of small amounts of the
completely unprotected seco-CPI, which is difficult to remove
acid to yield 9 (42.0 g, 0.10 mol, 77%) as colorless crystals. M.p. 207.68C; IR
1
(KBr): nÄ ˆ 3236, 3098, 1610, 1342, 1166 cm
;
1H NMR (200 MHz,
[D6]DMSO): d ˆ 3.29 (s, 3H, O ± CH3), 6.54 ± 6.60 (m, 2H, 3-H, 5-H), 7.20
(d, J ˆ 9.0 Hz, 1H, 6-H), 7.40 ± 7.66 (m, 6H, Ph ± H), 7.67 ± 7.76 (m, 4H, Ph ±
H), 9.20 (s, 1H, N ± H), 10.14 (s, 1H, N ± H); 13C NMR (50 MHz,
[D6]DMSO): d ˆ 55.13 (O ± CH3), 104.0 (C-3), 112.0 (C-5), 121.3 (C-1),
126.5 (C-2'', C-6''), 126.7 (C-2', C-6'), 126.9 (C-
6), 128.5 (C-3'', C-5''), 129.1 (C-3', C-5'), 132.3
(C-4''), 132.8 (C-4'), 136.6 (C-4), 139.3 (C-1''),
140.4 (C-1'), 153.2 (C-2); MS (70 eV): m/z
‡
‡
(%) ˆ 418 (13) [M ], 277 (100) [M SO2Ph ],
‡
‡
141 (27) [SO2Ph ], 77 (91) [C6H5 ], 43 (48)
[C2H3O ]; C19H18N2O5S2 (418.5): calcd
54.53, H 4.33; found C 54.60, H 4.33.
‡
C
N,N'-Dibenzenesulfonyl-5-bromo-2-methoxy-
1,4-phenylenediamine (10): N-bromosuccin-
imide (1.27 g, 7.17 mmol) was slowly added
with stirring to
a solution of 9 (3.00 g,
7.17 mmol) in THF (200 mL) at 788C. Stir-
ring was continued for 3 h, and the mixture
was allowed to warm to 208C. The solvent was
evaporated in vacuo, the residue washed with
water and recrystallized from acetic acid to
give 10 (3.50 g, 7.03 mmol, 95%) as colorless
crystals. M.p. 224.48C; IR (KBr): nÄ ˆ 3248,
Scheme 6. Synthesis of compound 3 (CPI ± SO2Ph). Reaction conditions: a) CSA, CH2Cl2, 2 h, 208C,
99%; b) BBr3, CH2Cl2, 93%; c) K2CO3, MeOH, 99%; d) Red-Al, toluene, 90%; e) Red-Al, toluene,
90%; f) DEAD, PPh3, THF, 49%.
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L. F. Tietze et al.
FULL PAPER
1
3068, 1602, 1344, 1160, 1042 cm
;
1H NMR (200 MHz, [D6]DMSO): d ˆ
N,N'-Diallyl-N,N'-dibenzenesulfonyl-6-bromo-2-methoxy-1,4-phenylene-
diamine (20): As in the preparation of 6, compound 20 was synthesized by
the reaction of 19 (1.50 g, 3.02 mmol), NaH (152 mg, 6.33 mmol), allyl-
bromide (0.53 mL, 6.03 mmol), and nBu4NI (20 mg) in THF (30 mL).
Recrystallization from ethanol gave 19 (1.40 g, 2.42 mmol, 80%) as
3.31 (s, 3H, O ± CH3), 6.59 (s, 1H, 3-H), 7.30 (s, 1H, 6-H), 7.48 ± 7.70 (m,
10H, Ph ± H); 13C NMR (50 MHz, [D6]DMSO): d ˆ 55.56 (O ± CH3), 109.9
(C-5), 111.2 (C-3), 125.0 (C-1), 126.5 (C-2'', C-6''), 126.8 (C-2', C-6'), 128.3
(C-4), 128.8 (C-3'', C-5''), 129.1 (C-3', C-5'), 132.7 (C-4'', C-4'), 132.8 (C-6),
‡
140.4 (C-1', C-1''), 151.6 (C-2); MS (70 eV): m/z (%) ˆ 497 (26) [M ], 356
colorless crystals. M.p. 104.28C; IR (KBr): nÄ ˆ 3086 (Ar± H), 1644
‡
‡
‡
1
ˆ
ˆ
(100) [M SO2Ph ], 141 (38) [SO2Ph ], 77 (72) [C6H5 ]; C19H17N2O5S2Br
(C C), 1448 (C ± H), 1350 (S O), 1168 (C ± O ± C), 1046 cm (Ar ± Br);
(497.3): calcd C 45.88, H 3.44; found C 45.94, H 3.48.
1H NMR (200 MHz, CDCl3): d ˆ 3.27 (s, 3H, O ± CH3), 3.83 ± 4.30 (m, 4H,
ˆ
2 Â CH2), 4.82 ± 5.14 (m, 4H, 2 Â CH CH2), 5.57 ± 5.89 (m, 2H, 2 Â
N,N'-Diallyl-N,N'-dibenzenesulfonyl-5-bromo-2-methoxy-1,4-phenylene-
diamine (6): A solution of 10 (2.00 g, 4.02 mmol) in THF (50 mL) was
added at 208C with stirring to a suspension of NaH (203 mg, 8.44 mmol) in
THF (10 mL), and after stirring for 1 h at 508C allylbromide (0.70 mL,
8.04 mmol) and nBu4NI (20 mg) were added at 208C. The mixture was
stirred under reflux for 5 h, then treated with saturated aqueous NH4Cl
(10 mL) and concentrated in vacuo. The residue was dissolved in CH2Cl2
(50 mL), washed with brine, dried over MgSO4, and concentrated in vacuo.
Recrystallization from EtOH yielded 6 (2.20 g, 3.82 mmol, 95%) as
ˆ
CH CH2), 6.57 (d, J ˆ 2.4 Hz, 1H, 3-H), 6.62 (d, J ˆ 2.4 Hz, 1H, 5-H),
7.36 ± 7.62 (m, 8H, Ph ± H), 7.69 ± 7.78 (m, 2H, Ph ± H); 13C NMR (50 MHz,
CDCl3): d ˆ 52.71, 53.39 (2  CH2), 55.42 (O ± CH3), 112.1 (C ± 3), 118.2,
ˆ
119.4 (2 Â CH CH2), 123.7 (C-5), 126.2 (C-6), 127.6 (C-2'', C-6''), 127.7
(C-2', C-6'), 128.1 (C-1), 128.5 (C-3'', C-5''), 128.9 (C-3', C-5'), 132.2, 132.4
ˆ
(2 Â CH CH2), 132.7 (C-4''), 133.1 (C-4'), 137.5 (C-1''), 140.7 (C-1', C-4),
‡
158.1 (C-2); MS (70 eV): m/z (%) ˆ 437 (12) [M ], 437 (100) [M
‡
‡
‡
SO2Ph ], 295 (6.3) [M 2 Â SO2Ph ], 77 (6) [C6H5 ]; C25H25N2O5S2Br
(578.3): calcd C 51.99 H 4.36; found C 52.26 H 4.20.
colorless crystals. M.p. 139.58C; IR (KBr): nÄ ˆ 3070 (Ar± H), 1642
(C C), 1354 (S O), 1168 (C ± O ± C), 1036 cm (Ar± Br); 1H NMR
1
(3-RS)-5-(Allylbenzenesulfonylamino)-1-benzenesulfonyl-6-methoxy-4-
iodo-3-iodomethyl-2,3-dihydro-1H-indole (11):
ˆ
ˆ
(200 MHz, [D6]DMSO): d ˆ 3.08 (s, 3H, O ± CH3), 4.12 (brd, J ˆ 6.0 Hz,
a) Starting from compound 6: A solution of tert-butyllithium in hexane
(0.41 mL, 0.70 mmol, 1.7m) was slowly added to a solution of 6 (200 mg,
0.34 mmol) and Cp2ZrMeCl (106 mg, 0.35 mmol) in dry degassed THF
(10 mL) at 788C under stirring, and stirring was continued for 1 h at
788C and then for 18 h at 208C. The solvent was evaporated in vacuo and
the residue dissolved in CH2Cl2 (20 mL). To this solution a suspension of
sublimed iodine (178 mg, 0.72 mmol) in CH2Cl2 (20 mL) was added slowly
at 08C and the mixture stirred for 1 h at 08C and for 36 h at 208C. The
mixture was filtered through Celite, the filtrate washed with saturated
aqueous Na2SO3 solution and brine, dried over MgSO4, and concentrated
in vacuo. The residue was chromatographed on silica gel (petroleum ether/
ethyl acetate ˆ 3:1) to afford 11 (153 mg, 0.20 mmol, 60%) as a brown
amorphous solid. Recrystallization from ethyl acetate afforded 11 as
colorless crystals.
ˆ
4H, 2 Â CH2) 4.96 ± 5.16 (m, 4H, 2 Â CH CH2), 5.58 ± 5.83 (m, 2H, 2 Â
ˆ
CH CH2), 6.30 (s, 1H, 3-H), 7.42 (s, 1H, 6-H), 7.52 ± 7.78 (m, 10H, Ph ± H);
13C NMR (50 MHz, [D6]DMSO): d ˆ 51.82, 53.52 (2  CH2), 55.19 (O ±
ˆ
CH3), 114.5 (C-3), 114.8 (C-5), 118.2, 119.6 (2 Â CH CH2), 126.9 (C-2'', C-
6''), 127.1 (C-1), 127.5 (C-2', C-6'), 128.8 (C-3'', C-5''), 129.2 (C-3', C-5'),
ˆ
ˆ
132.0 (CH CH2), 132.8 (C-4''), 133.0 (CH CH2), 133.3 (C-4'), 136.0 (C-3),
138.0 (C-1''), 138.2 (C-1'), 138.9 (C-4), 155.4 (C-2); MS (70 eV): m/z (%) ˆ
‡
‡
‡
‡
578 (15) [M ], 437 (100) [M SO2Ph ], 141 (48) [SO2Ph ], 77 (18) [C6H5 ];
C25H25N2O5S2Br (578.3): calcd C 51.99, H 4.36; found C 52.14, H 4.46.
3-Bromo-5-nitro-2-aminoanisole (17): N-bromosuccinimide (22.2 g,
125 mmol) was slowly added to a solution of 5-nitro-2-aminoanisole 8
(20.0 g, 119 mmol) in THF (150 mL) at 788C and the mixture stirred for
3 h at the same temperature. Stirring was continued at 208C for 20 h.
Evaporation of the solvent in vacuo and washing of the residue with water
gave 17 (28.2 g, 114 mmol, 96%) after recrystallization (ethanol, 100 mL)
as red crystals. M.p. 104.28C; IR (KBr): nÄ ˆ 3502 (N ± H), 3394 (N ± H),
1602 (Ar), 1502 (NO2), 1320 (NO2), 1284, 1234 cm 1 (C ± O ± C); 1H NMR
(200 MHz, CDCl3): d ˆ 3.98 (s, 3H, O ± CH3), 4.95 (brs, 2H, NH2), 7.63 (d,
J ˆ 2.5 Hz, 1H, 6-H), 8.10 (d, J ˆ 2.5 Hz, 1H, 4-H); 13C NMR (50 MHz,
[D6]DMSO): d ˆ 56.29 (O ± CH3), 103.2 (C ± 3), 104.5 (C-6), 121.7 (C-4),
135.8 (C-2), 143.0 (C-5), 145.0 (C-1); MS (70 eV): m/z (%) ˆ 264 (100)
b) Starting from compound 20: According to the above described
procedure, reaction of 20 (200 mg, 0.34 mmol), Cp2ZrMeCl (106 mg,
0.35 mmol) and
a solution of tert-butyllithium in hexane (0.41 mL,
0.70 mmol, 1.7m) and followed by quenching with iodine (267 mg,
1.08 mmol) gave 11 (94.3 mg, 0.13 mmol, 37%) as colorless crystals.
ˆ
M.p. 206.98C (decomposition); IR (KBr): nÄ ˆ 3070 (Ar± H), 1590 (C C),
1
1354 (S O), 1166 (C ± O ± C), 1072 cm (Ar ± I); 1H NMR (300 MHz,
ˆ
‡
‡
‡
CDCl3): d ˆ 2.34 (dd, J ˆ 10.0, 9.0 Hz, 1H, 3-CHa), 3.32 (s, 3H, O ± CH3),
3.34 ± 3.46 (m, 2H, 3-H, 3-CHb), 3.85 ± 4.00 (m, 2H, 2-Ha, 1'-Ha), 4.10 (d,
J ˆ 12.0 Hz, 1H, 2-Hb), 4.49 (dd, J ˆ 13.5, 6.0 Hz, 1H, 1'-Hb), 4.93 (d, J ˆ
[M ], 226 (34) [M NH2 ], 216 (34), 200 (19) [M NO2 ], 93 (37), 78 (80)
[Br ], 51 (24) [C4H3 ]; C7H7BrN2O3 (247.0): calcd: C 34.03, H 2.86; found C
33.98, H 2.89.
‡
‡
ˆ
ˆ
6.0 Hz, 1H, trans-CH CH2), 4.98 (s, 1H, cis-CH CH2), 5.83 ± 5.97 (mc, 1H,
N,N'-Dibenzenesulfonyl-6-bromo-2-methoxy-1,4-phenylenediamine (19):
Hydrazine hydrate (80%, 12.5 mL, 201 mmol) was added to a mixture of
17 (10.0 g, 40.5 mmol), activated carbon (4.60 g, 383 mmol), and FeCl3 ´
H2O (4.33 g, 1.60 mmol) in methanol (150 mL) over a period of 7 days
under reflux with stirring. Then ethyl acetate (200 mL) was added and the
solids were filtered off. The organic layer was washed with H2O (4 Â
100 mL) and brine (50 mL) and dried over Na2SO4. Evaporation of the
solvent gave crude 1,4-diamine 18 (8.61 g, 39.7 mmol, 98%) as a purple
solid. Owing to its sensitivity, the product was used without further
purification for the preparation of 19. Benzenesulfonyl chloride (14.0 g,
79.4 mmol) was added to a solution of 18 (8.61 g, 39.7 mmol) in dry
degassed pyridine (300 mL) and the mixture stirred for 3 h at 808C. After
concentration to a volume of about 100 mL, ice-cold aqueous hydrochloric
acid (500 mL, 5% HCl) was added, the resulting black oil separated and
crystallized from glacial acetic acid to give 19 (16.0 g, 32,2 mmol, 81%) as
colorless crystals. M.p. 208.58C (decomposition); IR (KBr): nÄ ˆ 3252 (N ±
ˆ
-CH CH2), 7.14 (s, 1H, 7-H), 7.48 ± 7.69 (m, 6H, Ph-H), 7.72 ± 7.79 (m, 2H,
Ph ± H), 7.82 (d, J ˆ 8.0 Hz, 2H, Ph ± H); 13C NMR (50 MHz, CDCl3): d ˆ
7.643 (CH2 ± I), 47.54 (C-3), 53.08 (N ± CH2), 55.34 (O-CH3), 55.37 (C-2),
ˆ
98.63 (C-7), 105.6 (C-4), 119.1 (CH CH2), 125.6 (C-5), 127.2 (C-2'', C-6''),
127.8 (C-2', C-6'), 128.5 (C-3'', C-5''), 129.4 (C-3', C-5'), 129.6 (C-3a), 132.3
ˆ
(C-4''), 132.8 (CH CH2), 134.0 (C-4'), 136.7 (C-7a), 140.9 (C-1'), 142.1 (C-
‡
‡
1''), 157.9 (C-6); MS (70 eV): m/z (%) ˆ 750 (12) [M ], 623 (5) [M I ], 609
‡
‡
‡
(100) [M SO2Ph ], 483 (13) [M SO2Ph I ], 77 (12) [C6H5 ];
C25H24N2O5S2I2 (750.0): calcd C 40.02, H 3.22; found C 39.65, H 3.46.
(3-RS)-5-(Allylbenzenesulfonylamino)-1-benzenesulfonyl-6-methoxy-4-
iodo-3-hydroxymethyl-2,3-dihydro-1H-indole (22): A suspension of com-
pound 11 (20.0 mg, 0.03 mmol) and Ag2O (6.30 mg, 0.03 mmol) on silica gel
in acetone and water (100:1) was stirred for 48 h at 208C. The solvent was
removed in vacuo and the residue dissolved in dichloromethane, washed
with water and brine, dried over MgSO4, and concentrated in vacuo.
Chromatography (petroleum ether/ethyl acetate ˆ 2:1) afforded 22
(18.2 mg, 28.5 mmol, 95%) as a colorless amorphous solid. IR (KBr): nÄ ˆ
H), 1596 (Ar), 1384 (S O), 1322 (C ± N), 1166 (C ± O ± C), 1044 cm 1 (Ar±
ˆ
Br); 1H NMR (200 MHz, CDCl3): 3.41 (s, 3H, O ± CH3), 6.13 (brs, 1H, N ±
H), 6.53 (brs, 1H, N ± H), 6.66 (d, J ˆ 2.5 Hz, 1H, 3-H), 6.77 (d, J ˆ 2.5 Hz,
1H, 5-H), 7.40 ± 7.66 (m, 8H, Ph ± H), 7.70 ± 7.83 (m, 2H, Ph ± H); 13C NMR
(50 MHz, [D6]DMSO): d ˆ 55.07 (O ± CH3), 102.0 (C-3), 114.4 (C-5), 119.6
(C-6), 126.1 (C-1), 126.4 (C-2'', C-6''), 126.7 (C-2', C-6'), 128.4 (C-3'', C-5''),
129.4 (C-3', C-5'), 132.0 (C-4''), 133.3 (C-4'), 138.7 (C-4), 139.0 (C-1''), 142.2
1
3480, 3090, 2926, 1594, 1352, 1166 cm 1; H NMR (300 MHz, CDCl3): d ˆ
1.50 (t, J ˆ 5.4 Hz, 1H, OH), 3.04 ± 3.16 (m, 1H, 3-CHa), 3.18 ± 3.27 (m, 1H,
3-CHb), 3.29 (s, 3H, O ± CH3), 3.77 ± 3.85 (m, 2H, 2-Ha, 3-H), 3.96 (dd, J ˆ
14.4, 8.4 Hz, 1H, 2'-Ha), 4.27 (dd, J ˆ 10.5, 1.5 Hz, 1H, 2-Hb), 4.37 (dd, J ˆ
ˆ
14.4, 8.4 Hz, 1H, 2'-Hb), 4.96 (dd, J ˆ 13.5, 1.8 Hz, 2H, CH CH2), 5.84 ±
‡
ˆ
(C-1'), 157.3 (C-2); MS (70 eV): m/z (%) ˆ 496 (8.0) [M ], 355 (100) [M
5.99 (m, 1H, CH CH2), 7.13 (s, 1H, 7-H), 7.47 ± 7.69 (m, 6H, Ph ± H), 7.70 ±
‡
‡
‡
‡
SO2Ph ], 215 (25) [M 2 Â SO2Ph ], 141 (21) [SO2Ph ], 77 (33) [C6H5 ];
7.77 (m, 2H, Ph ± H), 7.81 ± 7.86 (m, 2H, Ph ± H); 13C NMR (50 MHz,
C19H17N2O5S2Br (497.3): calcd C 45.88, H 3.44; found C 46.19, H 3.62.
CDCl3): d ˆ 46.98 (C-3), 52.77 (N ± CH2), 53.22 (C-2), 55.26 (O ± CH3),
1558
ꢀ WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
0947-6539/98/0408-1558 $ 17.50+.50/0
Chem. Eur. J. 1998, 4, No. 8

CC-1065 Pharmacophore
1554±1560
‡
‡
ˆ
62.48 (O ± CH2), 98.08 (C-7), 105.4 (C-4), 118.9 (CH CH2), 125.0 (C-5),
127.3 (C-2'', C-6''), 127.8 (C-2', C-6'), 127.9 (C-3a), 128.5 (C-3'', C-5''), 129.3
(70) [M SO2Ph ], 353 (100) [M SO2Ph C2H4O2 ], 212 (82) [M 2 Â -
‡
‡
SO2Ph C2H4O2 ], 77 (88) [C6H5 ]; C27H26N2O7S2 (554.6): calcd C 58.47, H
4.72; found C 58.55, H 4.86.
ˆ
(C-3', C-5'), 132.3 (C-4''), 133.0 (CH CH2), 133.8 (C-4'), 136.8 (C-7a), 141.0
‡
(C-1'), 142.8 (C-1''), 157.6 (C-6); MS (70 eV): m/z (%) ˆ 640 (8) [M ], 499
‡
‡
‡
(100) [M SO2Ph ], 144 (8) [SO2Ph ], 77 (75) [C6H5 ]; C25H25N2O6S2I
(1-RS)-6-Benzenesulfonyl-3-benzenesulfonyl-5-hydroxy-1-acetoxymethyl-
8-methyl-1,2-dihydro-3H-pyrrolo[3,2-e]indole (25): Boron tribromide
(1.00 mL, 1.00 mmol, 1m in dichloromethane) was added dropwise with
stirring to a solution of 24 (100 mg, 0.18 mmol) in dichloromethane (2 mL)
at 108C, and stirring was continued for 4 h. The reaction mixture was
diluted with water (5 mL) and dichloromethane (15 mL), the organic layer
was separated, washed with brine, dried over MgSO4, and concentrated in
vacuo. Flash chromatography of the residue (petroleum ether/ethyl
acetate ˆ 2:1) provided 25 (90.0 mg, 0.17 mmol, 93%) as an amorphous
solid. IR (KBr): nÄ ˆ 3342, 3070, 2960, 1738, 1614, 1360, 1168 cm 1; 1H NMR
(300 MHz, CDCl3): d ˆ 2.01 (s, 3H, OAc), 2.21 (s, 3H, 8-CH3), 3.10 (dd, J ˆ
10.0, 9.0 Hz, 1H, 1-CHa), 3.52 ± 3.78 (m, 2H, 1-H, 1-CHb), 4.06 (dd, J ˆ 11.5,
3.5 Hz, 1H, 2-Ha) 4.16 (d, J ˆ 11.5 Hz, 2-Hb), 7.15 (s, 1H, 7-H), 7.37 (s, 1H,
4-H), 7.38 ± 7.63 (m, 6H, Ph ± H), 7.76 (d, J ˆ 8.0 Hz, 2H, Ph ± H), 7.85 (d,
J ˆ 8.0 Hz, 2H, Ph ± H), 8.85 (s, 1H, Ph ± OH); 13C NMR (125 MHz,
CDCl3): d ˆ 11.23 (8-CH3), 20.75 (OAc), 38.17 (C-1), 53.67 (C-2), 65.48
(O ± CH2), 101.3 (C-4), 112.8 (C-8), 120.3 (C-8a), 120.5 (C-1a), 126.9, 127.3
(C-2'', C-6'', C-2', C-6'), 127.0 (C-7), 129.1, 129.5 (C-3'', C-5'', C-3', C-5'),
(640.5): calcd C 46.88, H 3.93; found C 47.02, H 3.96.
(3-RS)-5-(Allylbenzenesulfonylamino)-1-benzenesulfonyl-6-methoxy-4-
iodo-3-acetoxymethyl-2,3-dihydro-1H-indole (5): A mixture of 22 (200 mg,
0.31 mmol) and NaOAc (31.0 mg, 0.38 mmol) in acetic anhydride (2 mL)
was stirred for 1 h at 608C. The suspension was diluted with dichloro-
methane (10 mL), and the organic layer was washed with saturated
aqueous NaHCO3 solution and brine, dried over MgSO4, and concentrated
in vacuo. Flash chromatography of the residue (petroleum ether/ethyl
acetate ˆ 2:1) provided 5 (211 mg, 0.31 mmol, 99%) as a colorless solid. IR
1
(KBr): nÄ ˆ 3068, 2942, 1742, 1594, 1354), 1168 cm
;
1H NMR (300 MHz,
CDCl3): d ˆ 2.05 (s, 3H, OAc), 3.32 (s, 3H, OCH3), 3.34 ± 3.47 (m, 2H, 3-
CHa, 3-H), 3.80 (dd, J ˆ 10.5, 7.8 Hz, 1H, 3-CHb), 3.97 (dd, J ˆ 13.5, 8.0 Hz,
1H, 2-Ha), 4.11 (d, J ˆ 10.5 Hz, 1H, 2'-Ha), 4.24 ± 4.40 (m, 2H, 2'-Hb, 2-Hb),
ˆ
ˆ
4.94 (d, J ˆ 8.0 Hz, 1H, CH CHH), 4.98 (s, 1H, CH CHH), 5.81 ± 5.96 (m,
ˆ
1H, CH CH2), 7.14 (s, 1H, 7-H), 7.46 ± 7.70 (m, 6H, Ph ± H), 7.74 (d, J ˆ
7.5 Hz, 2H, Ph ± H), 7.82 (d, J ˆ 7.5 Hz, Ph ± H); 13C NMR (75 MHz,
CDCl3): d ˆ 20.79 (CH3), 43.83 (C-3), 53.00 (C-2), 53.15 (N ± CH2), 55.30
131.6 (C-5a), 133.4, 134.2 (C-4'', C-4'), 136.4 (C-3a), 136.6, 140.5 (C-1'', C-
ˆ
(O ± CH3), 63.62 (O ± CH2), 98.11 (C-7), 105.6 (C-4), 119.1 (CH CH2),
‡
ˆ
1'), 145.8 (C-5), 170.6 (C O); MS (70 eV): m/z (%) ˆ 540 (62) [M ], 467
125.3 (C-5), 127.0 (C-3a), 127.2 (C-2'', C-6''), 127.9 (C-2', C-6'), 128.5
(C-3'', C-5''), 129.4 (C-3', C-5'), 132.3 (C-4''), 132.7 (CH CH2), 134.0 (C-4'),
‡
‡
(50) [M C3H5O2 ], 339 (100) [M SO2Ph C2H4O2 ], 198 (42) [M 2 Â
ˆ
‡
SO2Ph C2H4O2 ]; C26H24N2O7S2 (540.6): calcd C 57.77, H 4.47; found C
ˆ
136.7 (C-7a), 141.0 (C-1'), 142.8 (C-1''), 157.9 (C-6), 170.5 (C O); MS
57.83, H 4.46.
‡
‡
(70 eV): m/z (%) ˆ 682 (7) [M ], 541 (100) [M SO2Ph ], 400 (2) [M 2 Â
‡
SO2Ph ]; C27H27N2O7S2I (682.6): calcd C 47.51, H 3.99; found C 47.97, H
(1-RS)-6-Benzenesulfonyl-3-benzenesulfonyl-5-hydroxy-1-hydroxymeth-
yl-8-methyl-1,2-dihydro-3H-pyrrolo[3,2-e]indole (26): A suspension of 25
(25.0 mg, 0.05 mmol) and potassium carbonate (19.0 mg, 0.13 mmol) in
methanol (2 mL) was stirred for 2 h at room temperature. The solvent was
evaporated in vacuo and the residue purified by column chromatography
(petroleum ether/ethyl acetate ˆ 1:1) to yield 26 (24.9 mg, 0.05 mmol,
4.11.
(1-RS)-6-Benzenesulfonyl-3-benzenesulfonyl-1-acetoxymethyl-8-methyli-
dene-1,2,7,8-tetrahydro-6H-pyrrolo[3,2-e]indole (23):
A mixture of 5
(100 mg, 0.15 mmol), Ag2CO3 (81.6 mg, 0.29 mmol), Pd(OAc)2 (7.00 mg,
0.03 mmol), PPh3 (16.0 mg, 0.06 mmol), and DMF (2 mL) was stirred at
208C for 3 h. After dilution with Et2O, the reaction mixture was filtered,
washed with water and brine, dried over MgSO4, and concentrated in
vacuo. The residue was purified by chromatography on silica gel
(petroleum ether/ethyl acetate ˆ 2:1) to give 23 (79.0 mg, 0.14 mmol,
90%) as an amorphous solid. IR (KBr): nÄ ˆ 3066, 2928, 1738, 1608, 1358,
1168 cm 1; 1H NMR (300 MHz, CDCl3): d ˆ 2.03 (s, 3H, OAc), 2.85 (t, J ˆ
10.1 Hz, 1H, 1-H), 3.40 ± 3.66 (m, 1H, 1-CHb), 3.70 ± 3.80 (m, 1H, 1-CHa),
3.76 (s, 3H, OCH3), 3.96 (dd, J ˆ 11.2, 3.6 Hz, 1H, 2-Ha), 4.12 (d, J ˆ
11.2 Hz, 1H, 2-Hb), 4.69 (s, 2H, 7-Ha, 7-Hb), 5.04 (s, 1H, 8-CHH), 5.28 (s,
1H, 8-CHH), 7.28 ± 7.36 (m, 2H, Ph ± H), 7.38 (s, 1H, 4-H), 7.45 ± 7.57 (m,
quant.) as an amorphous colorless solid. IR (KBr): nÄ ˆ 3354, 3066, 2926,
1
1612, 1356 cm
;
1H NMR (300 MHz, CDCl3): d ˆ 1.52 (brs, 1H, CH2 ±
OH), 2.19 (d, J ˆ 2.2 Hz, 1H, 8-CH3), 2.89 ± 3.08 (m, 1H, 1-H), 3.39 ± 3.55
(m, 2H, CH2 ± OH), 3.73 (dd, J ˆ 11.2, 8.9 Hz, 1H, 2-Ha), 4.20 (d, J ˆ
11.2 Hz, 1H, 2-Hb), 7.16 (d, J ˆ 2.2 Hz, 1H, 7-H), 7.39 (s, 1H, 4-H), 7.40 ±
7.62 (m, 6H, Ph ± H), 7.76 (dd, J ˆ 6.7, 1.8 Hz, 2H, Ph ± H), 7.87 (dd, J ˆ 6.7,
1.8 Hz, 2H, Ph ± H), 8.84 (s, 1H, Ph ± OH); 13C NMR (125 MHz, CDCl3):
d ˆ 11.51 (8-CH3), 41.24 (C-1), 53.71 (C-2), 65.19 (O ± CH2), 101.3 (C-4),
114.0 (C-8), 120.3 (C-8a), 120.5 (C-1a), 127.0, 127.4 (C-2'', C-6'', C-2', C-6'),
129.0 (C-7), 129.1, 129.5 (C-3'', C-5'', C-3', C-5'), 131.9 (C-5a), 133.3, 134.1
(C-4'', C-4'), 136.7 (C-3a), 136.6, 140.6 (C-1'', C-1'), 145.5 (C-5); MS (70 eV):
3H, Ph ± H), 7.58 ± 7.67 (m, 3H, Ph ± H), 7.80 (d, J ˆ 6.7 Hz, 2H, Ph ± H); 13
C
NMR (125 MHz, CDCl3): d ˆ 20.83 (CH3), 37.81 (C-1), 53.59 (C-2), 56.25
(O ± CH3), 57.47 (C-7), 63.41 (O ± CH2), 101.4 (C-4), 107.2 (8-CH2), 116.6
(C-1a), 127.3, 127.4 (C-2'', C-6'', C-2', C-6'), 128.5, 129.3 (C-3'', C-5'', C-3', C-
5'), 130.6 (C-5a), 131.3 (C-8), 132.7, 133.7 (C-4'', C-4'), 136.5 (C-3a),
‡
‡
m/z (%) ˆ 498 (17) [M ], 467 (37) [M CH3O ], 327 (29) [M SO2Ph
‡
‡
CH3O ], 218 (100) [M 2 Â SO2Ph CH3O ]; C24H22N2O6S2 (498.6): calcd
498.0919; found 498.0919 (MS).
ˆ
139.0 (C-1'), 140.8 (C-8a), 141.4 (C-1''), 151.7 (C-5), 170.7 (C O);
(1-RS)-3-Benzenesulfonyl-5-hydroxy-1-hydroxymethyl-8-methyl-1,2-dihy-
dro-3H-pyrrolo[3,2-e]indole (4):
‡
‡
MS (70 eV): m/z (%) ˆ 554 (30) [M ], 413 (100) [M SO2Ph ],
‡
‡
353 (7) [M SO2Ph C2H4O2 ], 212 (40) [M 2 Â SO2Ph C2H4O2 ], 77
a) Starting from compound 26: Sodium bis(2-methoxyethoxy)dihydroalu-
minate (Red-Al) (0.05 mL, 0.20 mmol, 70% in toluene) was added
dropwise at 208C to a stirred solution of 26 (11.0 mg, 0.02 mmol) in
toluene (3 mL). After 3 h the reaction mixture was diluted with phosphate
buffer (5 mL, pH 7.0) and ethyl acetate (10 mL). The organic layer was
separated, dried over MgSO4, and concentrated in vacuo. Flash chroma-
tography (petroleum ether/ethyl acetate ˆ 1:1) of the residue provided 4
(6.50 mg, 18.1 mmol, 91%) as a colorless solid.
‡
(27) [C6H5 ]; C27H26N2O7S2 (554.6): calcd C 58.47, H 4.72; found C 58.55,
H 4.86.
(1-RS)-6-Benzenesulfonyl-3-benzenesulfonyl-5-methoxy-1-acetoxymeth-
yl-1,2-dihydro-3H-pyrrolo[3,2-e]indole (24): A solution of 23 (33.0 mg,
0.06 mmol) and camphorsulfonic acid (27.0 mg, 0.12 mmol) in dichloro-
methane (5 mL) was stirred for 2 h at 208C. The mixture was washed with
water and brine, dried over MgSO4, and concentrated in vacuo. Flash
chromatography (petroleum ether/ethyl acetate ˆ 2:1) afforded 24
(33.3 mg, 0.06 mmol, 99%) as an amorphous solid. IR (KBr): nÄ ˆ 3066,
2956, 1740, 1604, 1358, 1170 cm 1; 1H NMR (300 MHz, CDCl3): d ˆ 2.06 (s,
3H, OAc), 2.32 (s, 3H, 8-CH3), 2.94 (t, J ˆ 10.5 Hz, 1H, 1-H), 3.68 (s, 3H,
OCH3), 3.61 ± 3.71 (m, 1H, 1-CHa), 3.78 (dd, J ˆ 10.5, 8.0 Hz, 1H, 1-CHb),
4.10 ± 4.18 (m, 2H, 2-Ha, 2-Hb), 7.21 (s, 1H, 7-H), 7.27 (s, 1H, 4-H), 7.40 ±
7.62 (m, 6H, Ph ± H), 7.76 (d, J ˆ 7.5 Hz, 2H, Ph ± H), 7.72 (d, J ˆ 7.5 Hz, 2H,
Ph ± H); 13C NMR (125 MHz, CDCl3): d ˆ 11.08 (8-CH3), 20.82 (OAc),
38.45 (C-1), 53.67 (C-2), 55.62 (O ± CH3), 65.75 (O ± CH2), 95.83 (C-4),
113.4 (C-8), 114.9 (C-8a), 122.5 (C-1a), 126.9, 127.2 (C-2'', C-6'', C-2', C-6'),
127.7 (C-7), 128.8, 129.1 (C-3'', C-5'', C-3', C-5'), 130.6 (C-5a), 133.1, 133.4
(C-4'', C-4'), 136.4 (C-3a), 139.0, 140.4 (C-1'', C-1'), 148.0 (C-5), 170.5
b) Starting from compound 25: Similarly, 25 (11.0 mg, 0.02 mmol) was
treated with Red-Al (0.05 mL, 0.20 mmol, 70% in toluene) in toluene
(3 mL) at 208C for 18 h to give 4 (6.49 mg, 18.0 mm) in 90% yield.
1
IR (KBr): nÄ ˆ 3340, 3060, 2926, 1614, 1348 cm
;
1H NMR (300 MHz,
CDCl3): d ˆ 1.38 (brs, 1H, CH2 ± OH), 2.29 (s, 3H, 8-CH3), 2.81 (t, J ˆ
9.0 Hz, 1H, 1-H), 3.53 ± 3.65 (m, 2H, 1-CH2), 3.85 (dd, J ˆ 12.0, 9.0 Hz, 1H,
2-Ha), 4.21 (d, J ˆ 9.0 Hz, 1H, 2-Hb), 5.66 (brs, 1H, Ph ± OH), 6.93 (s, 1H, 7-
H), 7.23 (s, 1H, 4-H), 7.37 ± 7.45 (m, 2H, Ph ± H), 7.49 ± 7.55 (m, 1H, Ph ± H),
7.83 (d, J ˆ 7.5 Hz, 2H, Ph ± H), 8.15 (brs, 1H, N ± H); MS (70 eV): m/z
‡
‡
‡
(%) ˆ 358 (85) [M ], 327 (100) [M CH2OH ], 217 (92) [M SO2Ph ],
‡
‡
187 (86) [M SO2Ph CH3O ], 142 (14) [SO2Ph ]; C18H18O4NS (358.5):
‡
‡
ˆ
(C O); MS (70 eV): m/z (%) ˆ 554 (85) [M ], 481 (32) [M C3H5O2 ], 413
calcd 358.09837; found 358.09837 (MS).
Chem. Eur. J. 1998, 4, No. 8
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1559

L. F. Tietze et al.
FULL PAPER
Acknowledgments: Generous financial support by the Deutsche For-
schungsgemeinschaft (SFB 416) and the Fonds der Chemischen Industrie is
gratefully appreciated.
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