A concise and efficient synthesis of seco-duocarmycin SA

Article abstract of DOI:10.1002/ejoc.200390094

A short and efficient synthesis of seco-duocarmycin SA (3), a highly potent cytostatic agent and direct precursor of the natural product duocarmycin SA (1), has been achieved. Starting from commercially available 2-methoxy-4-nitroaniline (4) the synthetic

Full text of DOI:10.1002/ejoc.200390094

FULL PAPER
A Concise and Efficient Synthesis of seco-Duocarmycin SA
Lutz F. Tietze,*[a] Frank Haunert,[a] Tim Feuerstein,[a] and Tobias Herzig[a]
Keywords: Cyclization / Indoles / Natural products / Radicals / Synthetic methods
A short and efficient synthesis of seco-duocarmycin SA (3), a
highly potent cytostatic agent and direct precursor of the nat-
ural product duocarmycin SA (1), has been achieved. Start-
ing from commercially available 2-methoxy-4-nitroaniline (4)
the synthetic protocol contains a Fischer indole synthesis to
introduce the heterocyclic scaffold and a radical 5-exo-trig
cyclization to furnish the (chloromethyl)indoline ring system
as key reactions.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
candidate for cancer treatment. The cytotoxicity of 1 as the
structurally and biologically related (ϩ)-CC-1065[4] (2) is
caused by an alkylation of N-3 of adenine in AT-rich parts
of the minor groove of the DNA by reaction with the spiro-
[cyclopropane-cyclohexadienone] moiety in 1 and 2.[3]
Duocarmycin SA (1) seems to be superior to CC-1065
(2) due to the lack of a delayed fatal hepatotoxicity associ-
ated with (ϩ)-CC-1065.[3] Moreover, (ϩ)-duocarmycin SA
is the most stable member of this class of agents and, ac-
cording to a correlation between solvolytic stability and
cytotoxic potency, it is also the most potent one. However,
seco compounds of 1 or 2, such as 3, possess a similar al-
kylating selectivity and efficiency as the corresponding nat-
ural products[5] since they can form the spiro[cyclopropane]
moiety in situ by an intramolecular Winstein cyclization.[6]
In studies that culminated in the total synthesis of (ϩ)- and
ent-(Ϫ)-seco-duocarmycin SA (1) the corresponding seco
compounds were the direct precursors.[7,8] On the other
hand, glycosylated seco analogues of duocarmycin and CC-
1065 are highly promising compounds for the selective
treatment of cancer in an antibody-directed enzyme pro-
drug therapy.[9Ϫ12] Therefore, seco compounds are also
highly interesting and promising synthetic targets. However,
so far a concise and practical approach towards 3 starting
from cheap, commercially available substrates is still miss-
ing. Here we describe a facile and efficient preparation of
seco-duocarmycin SA (3) starting from 2-methoxy-4-nitro-
aniline (4).
It has been shown in various studies that the natural anti-
biotic (ϩ)-duocarmycin SA (1), which was first isolated
from Streptomyces DO-113 in 1990,[1] is a highly potent
cytostatic agent (Scheme 1).[2] Compound 1 exhibits an ex-
traordinarily high cytotoxicity with an IC50 of 10 p (can-
cer line L1210)[3] and is thus considered to be a powerful
Results and Discussion
Scheme 1. Structures of (ϩ)-duocarmycin SA (1), (ϩ)-CC-1065 (2)
and seco-duocarmycin SA (3)
Diazotation of commercially available 2-methoxy-4-
nitroaniline (4) followed by instantaneous reduction of the
formed diazonium salt provided the corresponding hydra-
zine (Scheme 2). Further treatment with methyl pyruvate
yielded the hydrazone 5 very cleanly with an overall yield
of 69%.
[a]
Institut für Organische Chemie der Georg August Universität
Göttingen,
Tammannstrasse 2, 37077 Göttingen, Germany
Fax: (internat.) ϩ 49-551/399476
E-mail: ltietze@gwdg.de
562
 2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0203Ϫ0562 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2003, 562Ϫ566

A Concise and Efficient Synthesis of seco-Duocarmycin SA
FULL PAPER
Scheme 3. (a) NaH, DMF, room temp., 30 min; (E/Z)-1,3-dichloro-
propene, room temp., 12 h, 92%); (b) TTMSS, AIBN, benzene, 80
°C, 3 h, 79%; (c) 4  HCl/EtOAc, 2 h, room temp.; TMI-CO2H,
EDC, DMF, room temp., 18 h, 51%; (d) NH4HCO2, Pd/C, THF,
40 °C, 2 h, 91%
Scheme 2. (a) NaNO2; HCl, Ϫ10 °C, 5 min, SnCl2, Ϫ20 °C, 1 h,
70%; (b) NaOAc, methyl pyruvate, MeOH, room temp., 16 h, 99%;
(c) PPA, xylene, 120 °C, 18 h, 64%; (d) AlCl3, CH2Cl2, room temp.,
72 h, 70%; (e) BnBr, K2CO3, acetone, 40 °C, 8 h, 88%; (f) Boc2O,
DMAP, THF, room temp., 1 h, 98%; (g) Lindlar catalyst, quinoline,
EtOAc, H2, room temp., 18 h, 91%; (h) Boc2O, THF, room temp.,
18 h, 89%; (i) NBS, THF, Ϫ78 °C, 4 h, 88%
amine hydrochloride, which was then directly coupled with
5,6,7-trimethoxyindolecarboxylic acid in the presence of
EDC in DMF to give 12 in 51% yield. Finally, the benzyl
protecting group was removed by transfer hydrogenolysis
with NH4HCO2 as hydrogen donor and palladium on char-
coal as catalyst to give seco-duocarymcin SA (3) in 91%
yield.
The structures of the newly formed compounds were
mainly determined by NMR spectroscopy. The identity of
the final product was verified by comparison with the spec-
troscopic data found in the literature.[7]
A subsequent Fischer indole cyclization occurred on
heating 5 at 120 °C for 18 h in the presence of polyphos-
phoric acid and xylene as co-solvent to give 6 in 64%
yield.[13] During our investigations we encountered difficult-
ies to hydrolyse the methyl ether by standard procedures at
a later stage of the synthesis; therefore, we cleaved the
methyl ether with AlCl3 at this early point to switch to a
benzyl ether as a more feasible protecting group. The O-
benzyl-protected indole 7 was then treated with di-tert-butyl
dicarbonate to give the corresponding N-Boc-protected in-
dole, which, on reduction of the nitro group with Lindlar
catalyst and quinoline, led to 8 in 89% yield over two steps.
The protection of the amino moiety as its carbamate and
subsequent regioselective bromination with NBS at Ϫ78 °C
provided 9 in 78% overall yield. The bromination occurred
completely regioselectively at C-4 of the indole moiety with-
out the formation of any by-products.
Conclusion
The combination of a Fischer indole synthesis and a 5-
exo-trig radical cyclization has been shown to allow an effi-
cient generation of the tricyclic duocarmycin scaffold. With
this new synthetic protocol an excellent access to seco-duo-
carmycin SA (3) has been developed.
Experimental Section
After deprotonation of the NHBoc group in 9 with NaH,
alkylation with (E/Z)-1,3-dichloro-2-propene furnished the
corresponding N-(3-chloropropenyl)indole 10. This com-
pound was treated with tris(trimethylsilyl)silane[14] and
General: All reactions were performed under nitrogen or argon in
flame-dried flasks, and the reactants were introduced by syringe.
All solvents were dried by standard methods. All reagents obtained
catalytic amounts of AIBN in deoxygenated benzene at 80 from commercial sources were used without further purification.
°C in a radical 5-exo-trig cyclization[15] to generate the fully
Thin-layer chromatography was performed on precoated silica gel
SIL G/UV254 plates (MachereyϪNagel GmbH & Co. KG), and
silica gel 32Ϫ63 (0.032Ϫ0.064 mm) (MachereyϪNagel GmbH &
functionalized seco-duocarmycin scaffold 11 in 73% over
two steps (Scheme 3). Radical cyclization with Bu3SnH as
Co. KG) was used for column chromatography. UV/Vis spectra
radical donor is less suitable due to the high toxicity of the
were taken in CH3CN with a PerkinϪElmer Lambda 2 spectro-
reagent and the tedious separation of tin-containing com-
meter. IR spectra were recorded as KBr pellets or as films with a
pounds from the final product.
Bruker IFS 25 spectrometer. 1H and 13C NMR spectra were re-
corded with a Varian XL 200, VXR 200 and VXR 500 or a Bruker
AMX-300 with tetramethylsilane (TMS) as internal standard in
[D6]acetone, [D]chloroform or [D6]DMSO. The multiplicities of the
Coupling with the DNA-binding subunit of duocarmycin
SA Ϫ the trimethoxyindole (TMI) moiety Ϫ proceeded un-
der standard conditions. First, both Boc groups were re-
moved under acidic conditions to give the corresponding 13C NMR peaks were determined with the APT pulse sequence.
Eur. J. Org. Chem. 2003, 562Ϫ566
563

L. F. Tietze, F. Haunert, T. Feuerstein, T. Herzig
FULL PAPER
Mass spectra were measured at 70 eV with a Varian MAT 311A,
high-resolution mass spectra with a Varian MAT 731 instrument.
The following abbreviations are used in the text: EtOAc ϭ ethyl
acetate, PE ϭ petroleum ether.
NMR (50.3 MHz, [D6]DMSO): δ ϭ 51.9 (OCH3), 102.0 (C-3),
110.6 (C-6), 110.8 (C-4), 126.8 (C-2), 129.9 (C-7a), 131.0 (C-3a),
142.2 (C-7), 144.2 (C-5), 160.8 (CϭO) ppm. MS (70 eV, EI): m/z
(%) ϭ 236 (100) [Mϩ].
Methyl 2-[(2-Methoxy-4-nitrophenyl)hydrazono]propanoate (5): A
2. Protection as the Benzyl Ether: K2CO3 (55 mg, 400 µmol) and,
suspension of 2-methoxy-4-nitroaniline (4) (500 mg, 3.0 mmol) in dropwise, benzyl bromide (0.02 mL, 200 µmol) were added at room
concd. HCl (150 mL) was treated carefully with NaNO2 (216 mg, temp. to a solution of the phenol (45 mg, 190 µmol) in acetone
3.0 mmol) in water (150 mL) at Ϫ10 °C internal temperature. The (15 mL). The reaction mixture was stirred for 8 h at 40 °C, washed
resulting yellow solution was added to a Ϫ30 °C cold solution of
tin() chloride dihydrate (2.0 g, 9.0 mmol) in concd. HCl (100 mL)
with brine (100 mL) and extracted with ethyl acetate. After drying
of the extracts with Na2SO4, the solvents were removed in vacuo
and stirred for an additional hour at Ϫ20 °C. The reaction mixture and the residue purified by column chromatography (EtOAc/PE,
was then allowed to warm to room temperature and the precipitate
was filtered off and dried. The filtrate was dissolved in methanol
1:4) to afford 7 (55 mg, 167 µmol, 88%) as a yellow oil. IR (film):
ν˜ ϭ 3327, 3295 (NϪH), 2924, 2853 (CϪH), 1704 (CϭO), 1522,
and treated with NaOAc (297 mg, 3.6 mmol) and methyl pyruvate 1440 (CH2, CH3) cmϪ1. UV (CH3CN): λmax (lg ε) ϭ 209 (4.4), 266
(0.31 mg, 0.26 mL, 3.0 mmol). After vigorous stirring for 18 h, the (4.3), 282 (4.3), 368 (3.7) nm. 1H NMR (200 MHz, CDCl3): δ ϭ
yellow precipitate was filtered off, washed with cold methanol and
dried in vacuo to afford 553 mg of 5 (2.1 mmol, 69%). IR (KBr):
3.96 (s, 3 H, OCH3), 5.29 (s, 2 H, OCH2), 7.35 (d, J ϭ 2.2 Hz, 1 H,
3-H), 7.42Ϫ7.51 (m, 5 H, Ar-H), 7.72 (d, J ϭ 1.9 Hz, 1 H, 4-H),
ν˜ ϭ 3333 (NH), 2956 (CϪH), 1732 (CϭO), 1579 (CϭC), 1527, 8.36 (d, J ϭ 1.9 Hz, 1 H, 6-H), 9.34 (br. s, 1 H, NH) ppm. 13C
1501, 1473 (CH2, CH3) cmϪ1. UV (CH3CN): λmax (lg ε) ϭ 201 NMR (75.5 MHz, CDCl3): δ ϭ 52.4 (OCH3), 71.0 (OCH2), 100.3
(4.3), 239 (3.8), 247 (3.8), 292 (3.8), 382 (4.4), 385 (4.4) nm. 1H (C-6), 110.9 (C-4), 113.1 (C-3), 126.6 (C-2*), 128.2, 128.8, 128.9
NMR (200 MHz, CDCl3): δ ϭ 2.18 (s, 3 H, CH3), 3.90 (s, 3 H,
(ArϪCϪH), 129.6 (C-3a*), 130.8 (C-7a*), 135.2 (Ar-C), 143.1 (C-
OCH3), 4.05 (s, 3 H, OCH3), 7.62 (d, J ϭ 9.0 Hz, 1 H, 6-H), 7.76 5), 145.1 (C-7), 161.3 (CϭO) ppm. MS (70 eV, EI): m/z (%) ϭ
(d, J ϭ 2.2 Hz, 1 H, 3-H), 7.95 (dd, J ϭ 9.0, 2.2 Hz, 1 H, 5-H)
326 (10) [Mϩ], 91 (100) [C7H7ϩ]. C17H14N2O5 (326.30): calcd. C
ppm. 13C NMR (75.5 MHz, CDCl3): δ ϭ 10.8 (CH3), 52.7 (OCH3), 62.57, H 4.32; found C 62.89, H 4.03.
56.3 (4-OCH3), 105.8 (C-3), 112.2 (C-5), 118.7 (C-6), 137.4 (C-1),
Methyl 5-Amino-7-(benzyloxy)-1-(tert-butoxycarbonyl)indole-2-
carboxylate (8)
138.2 (C-4), 141.5 (C-2), 145.1 (CϭN), 165.2 (CϭO) ppm. MS
(70 eV, EI): m/z (%) ϭ 267 (100) [Mϩ]. C11H13N3O5 (267.24): calcd.
C 49.43, H 4.90; found C 49.12, H 4.84.
1. Protection of the Indole: A solution of 7 (720 mg, 2.20 mmol) in
THF (50 mL) was treated with di-tert-butyl dicarbonate (720 mg,
3.30 mmol) and catalytic amounts of DMAP and stirred for 1 h at
room temp. The mixture was then quenched with brine and ex-
tracted with ethyl acetate, and the extracts were washed with water
and brine and dried with Na2SO4. The solution was concentrated
under reduced pressure and the residue purified by flash chromato-
graphy (EtOAc/PE, 1:2) to afford the N-Boc-protected indole
(855 mg, 2.16 mmol, 98%) as a yellow oil.
Methyl 7-Methoxy-5-nitro-1H-indole-2-carboxylate (6): A stirred
suspension of polyphosphoric acid (PPA) (3 g) in xylene (100 mL)
was treated with 5 (2.0 g, 7.5 mmol) and heated at 120 °C for 18 h.
The solvent was decanted and the residue thoroughly washed with
xylene and CH2Cl2. The combined organic layers were then washed
with water and dried with Na2SO4. Removal of the solvent and
purification by column chromatography (EtOAc/PE, 1:1) yielded
1.2 g (4.8 mmol, 64%) of 6 as an orange solid. IR (KBr): ν˜ ϭ 3314
(NϪH), 3103, 2952 (CϪH), 1708 (CϭO), 1588 (CϭC), 1526, 1434
(CH2, CH3) cmϪ1. UV (CH3CN): λmax (lg ε) ϭ 213 (4.3), 265 (4.2),
282 (4.2), 329 (3.7), 382 (3.7) nm. 1H NMR (200 MHz, CDCl3):
δ ϭ 3.87 (s, 3 H, OCH3), 4.06 (s, 3 H, OCH3), 7.33 (d, J ϭ 2.5 Hz,
1 H, 3-H), 7.61 (d, J ϭ 1.5 Hz, 1 H, 6-H), 8.34 (d, J ϭ 1.5 Hz, 1 H,
4-H), 9.32 (br. s, 1 H, NH) ppm. 13C NMR (50.3 MHz, CDCl3):
δ ϭ 52.4 (OCH3), 56.1 (4-OCH3), 99.5 (C-3), 110.9 (C-6), 113.0
(C-4), 126.7, 129.7, 130.9 (C-2, C-3a, C-7a), 143.6, 146.2 (C-5, C-
7), 161.4 (CϭO) ppm. MS (70 eV, EI): m/z (%) ϭ 250 (100) [Mϩ].
C11H10N2O5 (250.21): calcd. C 250.0590; found 250.0600.
Methyl 7-(Benzyloxy)-1-(tert-butoxycarbonyl)-5-nitroindole-2-carb-
oxylate: IR (film): ν˜ ϭ 3425 (NϪH), 3101, 2982, 2951 (CϪH),
1768, 1724 (CϭO), 1516 (CϭC), 1438, 1372 (CH2, CH3) cmϪ1. UV
(CH3CN): λmax (lg ε) ϭ 211 (4.4), 276 (4.4) nm. 1H NMR
(200 MHz, CDCl3): δ ϭ 1.47 [s, 9 H, C(CH3)3], 3.94 (s, 3 H,
OCH3), 5.32 (s, 2 H, OCH2), 7.34Ϫ7.39 (m, 6 H, 3-H, Ar-H), 7.46
(d, J ϭ 1.9 Hz, 1 H, 4-H), 8.26 (d, J ϭ 1.9 Hz, 1 H, 6-H) ppm. 13
C
NMR (75.5 MHz, CDCl3): δ ϭ 27.1 [C(CH3)3], 52.4 (OCH3), 71.1
(OCH2), 86.4 [C(CH3)3], 101.9 (C-6), 112.3 (C-4), 112.5 (C-3),
126.2 (C-7a*), 127.9, 128.5, 128.6 (Ar-CH), 129.8 (C-2*), 129.9 (C-
3a*), 134.9 (Ar-C), 143.3, 145.4 (C-5, C-7), 149.1, 160.3 (CϭO)
ppm. MS (70 eV, EI): m/z (%) ϭ 426 (63) [Mϩ], 91 (100) [C7H7ϩ].
Methyl 7-(Benzyloxy)-5-nitro-1H-indole-2-carboxylate (7)
1. Cleavage of the Methyl Ether: A solution of 6 (50 mg, 200 µmol)
in CH2Cl2 (50 mL) was treated with AlCl3 (134 mg, 1.0 mmol) at
room temp. and stirred for 72 h. The reaction was quenched by
careful addition of ice/water and extracted with ethyl acetate. After
drying of the extracts with Na2SO4, the solvents were removed in
vacuo and the residue purified by column chromatography (EtOAc/
PE, 1:2) to afford the corresponding phenol (33 mg, 139 µmol,
70%) as a brown solid.
2. Reduction of the Nitro Group: The nitroindole (900 mg,
2.10 mmol) was dissolved in ethyl acetate (150 mL), and Lindlar
catalyst (294 g) and quinoline (0.30 mL, 294 mg, 2.28 mmol) were
added. The suspension was stirred under hydrogen at room temp.
for 16 h. The solid was removed by filtration through Celite and
the solution was concentrated in vacuo. Purification by column
chromatography (EtOAc/PE, 1:1) yielded 8 (756 mg, 1.91 mmol,
91%) as a brown oil. IR (film): ν˜ ϭ 3367 (NϪH), 3004, 2978
Methyl 7-Hydroxy-5-nitro-1H-indole-2-carboxylate: IR (KBr): ν˜ ϭ (CϪH), 1764, 1716, 1628 (CϭO), 1581 (CϭC), 1437, 1370 (CH2,
3303 (NϪH), 1711 (CϭO), 1523, 1404 (CH2, CH3) cmϪ1. UV
CH3) cmϪ1. UV (CH3CN): λmax (lg ε) ϭ 209 (4.5), 229 (4.3), 246
(CH3CN): λmax (lg ε) ϭ 215 (4.2), 267 (4.2), 283 (4.3) nm. 1H NMR (4.4), 291 (4.1), 361 (3.5) nm. 1H NMR (200 MHz, CDCl3): δ ϭ
(200 MHz, [D6]DMSO): δ ϭ 3.87 (s, 3 H, OCH3), 7.38 (d, J ϭ 1.38 [s, 9 H, C(CH3)3], 3.88 (s, 3 H, OCH3), 5.13 (s, 2 H, OCH2),
2.0 Hz, 1 H, 6-H), 7.43 (d, J ϭ 2.2 Hz, 1 H, 4-H), 8.19 (d, J ϭ
7.04 (s, 1 H, 3-H), 7.11 (s, 1 H, 4-H), 7.26Ϫ7.41 (m, 6 H, 6-H, Ar-
1.8 Hz, 1 H, 3-H), 10.54 (s, 1 H, NH), 12.25 (s, 1 H, OH) ppm. 13
C
H) ppm. 13C NMR (75.5 MHz, CDCl3): δ ϭ 27.2 [C(CH3)3], 51.9
564
Eur. J. Org. Chem. 2003, 562Ϫ566

A Concise and Efficient Synthesis of seco-Duocarmycin SA
FULL PAPER
(OCH3), 70.3 (OCH2), 84.6 [C(CH3)3], 98.1 (C-6), 100.0 (C-4), Na2SO4. The solution was concentrated under reduced pressure
110.4 (C-3), 122.5 (C-7a), 127.4, 127.7 (Ar-CH), 127.9 (C-2*), 128.5 and the residue was purified by flash chromatography (EtOAc/PE,
(Ar-CH), 128.5 (C-3a*), 136.5 (Ar-C), 141.7 (C-5), 146.2 (C-7),
150.7, 161.24 (CϭO) ppm. MS (70 eV, EI): m/z (%) ϭ 396 (36)
[Mϩ], 296 (100) [Mϩ Ϫ C5H8O2]. C22H24N2O5 (396.44): calcd.
396.1685; found 396.1685.
1:2). The alkylated indole 10 (423 mg, 652 µmol, 92%) was ob-
tained as a yellow oil as a mixture of rotamers.
Methyl (E/Z)-7-(Benzyloxy)-4-bromo-1-(tert-butoxycarbonyl)-5-
[(tert-butoxycarbonyl)(3Ј-chloroprop-2Ј-enyl)amino]indole-2-carb-
oxylate (10): IR (film): ν˜ ϭ 3066, 2980 (CϪH), 1774, 1726 (CϭO),
1575 (CϭC), 1543, 1454, 1371 (CH2, CH3) cmϪ1. UV (CH3CN):
λmax (lg ε) ϭ 249 (4.4), 293 (3.9), 323 (3.5) nm. 1H NMR
(200 MHz, CDCl3): δ ϭ 1.25, 1.27 [s, 9 H, C(CH3)3], 1.29, 1.39 [s,
9 H, C(CH3)3], 3.83Ϫ3.93 (m, 5 H, OCH3, 1Ј-H2), 5.24 (s, 2 H,
OCH2), 5.89Ϫ6.10 (m, 2 H, 2Ј-H, 3Ј-H), 7.17 (s, 1 H, 3-H),
7.27Ϫ7.46 (m, 6 H, 6-H, Ar-H) ppm. 13C NMR (75.5 MHz,
CDCl3): δ ϭ 27.2, 28.1 [C(CH3)3], 45.9 (C-1Ј), 52.2 (OCH3), 70.6
(OCH2), 80.5, 85.8 [C(CH3)3], 107.8 (C-4), 109.9 (C-6), 111.8 (C-
3), 120.4, 121.5 (C-2Ј, C-3Ј), 127.3 (C-7a), 127.4, 128.2, 128.7 (Ar-
CH), 135.7 (Ar-C), 135.8 (C-2), 144.5 (C-3a), 149.7 (C-5), 154.3
(C-7), 160.7, 160.7, 171.1 (CϭO) ppm. MS (70 eV, EI): m/z (%) ϭ
648 (5) [Mϩ], 91 (100) [C7H7ϩ].
Methyl 7-(Benzyloxy)-4-bromo-1-(tert-butoxycarbonyl)-5-[(tert-but-
oxycarbonyl)amino]indole-2-carboxylate (9)
1. Protection of the Amino Group: A solution of 8 (475 mg,
1.2 mmol) in THF (150 mL) was treated with di-tert-butyl dicar-
bonate (786 mg, 3.60 mmol) and stirred for 18 h at room temp. The
mixture was quenched with brine, extracted with ethyl acetate, and
the extracts were washed with water and brine and dried with
Na2SO4. The solvent was evaporated under reduced pressure and
the residue purified by flash chromatography (EtOAc/PE, 1:2) to
yield the corresponding carbamate (529 mg, 1.07 mmol, 89%) as a
yellow oil.
Methyl 7-(Benzyloxy)-1-(tert-butoxycarbonyl)-5-[(tert-butoxycar-
bonyl)amino]indole-2-carboxylate: IR (film): ν˜ ϭ 3356 (NϪH), 2979
(CϪH), 1769, 1722 (CϭO), 1590 (CϭC), 1531, 1456, 1369 (CH2,
CH3) cmϪ1. UV (CH3CN): λmax (lg ε) ϭ 217 (4.4), 251 (4.6), 292
(4.1), 333 (3.5), 288 (4.1) nm. 1H NMR (200 MHz, CDCl3): δ ϭ
1.44 [s, 9 H, C(CH3)3], 1.51 [s, 9 H, C(CH3)3], 3.89 (s, 3 H, OCH3),
5.21 (s, 2 H, OCH2), 6.42 (br. s, 1 H, NH), 6.82 (d, J ϭ 1.5 Hz,
1 H, 4-H), 7.09 (s, 1 H, 3-H), 7.27Ϫ7.42 (m, 6 H, 6-H, Ar-H) ppm.
13C NMR (75.5 MHz, CDCl3): δ ϭ 27.2, 28.4 [C(CH3)3], 51.9
(OCH3), 70.5 (OCH2), 80.4, 84.9 [C(CH3)3], 101.6 (C-6), 103.7 (C-
4), 111.2 (C-3), 124.4 (C-7a), 127.7 (Ar-CH), 127.9 (C-2*), 128.0
(Ar-CH), 128.1 (C-3a*), 128.5 (Ar-CH), 133.1 (Ar-C), 136.2 (C-5),
145.7 (C-7), 150.3, 153.0, 161.24 (CϭO) ppm. MS (70 eV, EI): m/z
(%) ϭ 496 (18) [Mϩ], 396 (25) [Mϩ Ϫ C5H8O2], 91 (100) [C7H7ϩ].
2. Radical Cyclization: A solution of the alkylated indole 10
(429 mg, 662 µmol) in benzene (20 mL) was degassed thoroughly
and treated with tris(trimethylsilyl)silane (TTMSS) (0.22 mL,
176 mg, 707 µmol) and AIBN (25 mg, 153 µmol). After 3 h of stir-
ring at 80 °C, the volatiles were removed in vacuo and the residue
was purified by flash chromatography (EtOAc/PE, 1:2) to give 11
(299 mg, 523 µmol, 79%) as a yellow oil.
Methyl (1R/S)-5-(Benzyloxy)-3,6-bis(tert-butoxycarbonyl)-1-
(chloromethyl)-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylate
(11): IR (film): ν˜ ϭ 3031, 2978, 2929 (CϪH), 1771, 1722 (CϭO),
1591 (CϭC), 1539, 1369 (CH2, CH3) cmϪ1. UV (CH3CN): λmax (lg
ε) ϭ 251 nm (4.4), 293 (3.9), 332 (3.5) nm. 1H NMR (200 MHz,
CDCl3): δ ϭ 1.43 [s, 9 H, C(CH3)3], 1.51 [s, 9 H, C(CH3)3],
3.80Ϫ4.14 (m, 5 H, 1-H, 2-H2, 9-H2), 3.90 (s, 3 H, OCH3), 5.24 (s,
2 H, OCH2), 7.08Ϫ7.21 (m, 3 H, Ar-H), 7.27Ϫ7.44 (m, 4 H, Ar-H)
ppm. 13C NMR (75.5 MHz, CDCl3): δ ϭ 27.1, 28.5 [C(CH3)3],
42.0 (C-1), 46.8 (C-2), 52.1 (OCH3), 52.9 (C-9), 70.7 (OCH2), 85.3
[C(CH3)3], 97.9 (C-6), 107.7 (C-3), 122.3 (C-7a), 123.7 (C-4), 124.5
(C-2), 127.3, 128.1, 128.5 (Ar-CH), 136.1 (Ar-C), 146.3, 150.1,
152.3 (C-3a, C-5, C-7), 160.8, 171.2 (CϭO) ppm. MS (70 eV, EI):
m/z (%) ϭ 570 (20) [Mϩ], 470 (15) [Mϩ Ϫ C5H8O2], 91 (100)
[C7H7ϩ].
2. Bromination: The carbamate (450 mg, 907 µmol) was dissolved
in THF (150 mL) and N-bromosuccinimide was slowly added with
stirring at Ϫ78 °C. The reaction mixture was allowed to warm to
room temperature, and then extracted with EtOAc and dried with
Na2SO4. Concentration in vacuo and purification by column chro-
matography yielded 9 (459 mg, 798 µmol, 88%) as a light yellow
oil. IR (film): ν˜ ϭ 3342 (NϪH), 2978 (CϪH), 1761, 1728 (CϭO),
1579 (CϭC), 1545, 1455, 1368 (CH2, CH3) cmϪ1. UV (CH3CN):
λmax (lg ε) ϭ 216 (4.4), 249 (4.6), 295 (4.1), 327 (3.7) nm. 1H NMR
(200 MHz, CDCl3): δ ϭ 1.39 [s, 9 H, C(CH3)3], 1.53 [s, 9 H,
C(CH3)3], 3.90 (s, 3 H, OCH3), 5.24 (s, 2 H, OCH2), 6.89 (br. s,
1 H, NH), 7.17 (s, 1 H, 3-H), 7.32Ϫ7.46 (m, 5 H, Ar-H), 7.87 (s,
1 H, 6-H) ppm. 13C NMR (75.5 MHz, CDCl3): δ ϭ 27.1, 28.3
[C(CH3)3], 52.1 (OCH3), 70.9 (OCH2), 80.9, 85.5 [C(CH3)3], 101.9
(C-4), 102.0 (C-6), 110.8 (C-3), 123.9, 127.8, 127.9 (C-2, C-3a, C-
7a), 128.2, 128.5, 128.5 (Ar-CH), 131.2 (Ar-C), 135.8 (C-5), 145.4
(C-7), 149.7, 152.7, 160.7 (CϭO) ppm. MS (70 eV, EI): m/z (%) ϭ
574 (10) [Mϩ], 474 (15) [Mϩ Ϫ C5H8O2], 91 (100) [C7H7ϩ].
C27H31BrN2O7 (575.45): calcd. 574.1314; found 574.1314.
3. Coupling with the TMI Group: Compound 11 (127 mg, 229 µmol)
was dissolved in 4  HCl in EtOAc (10 mL) and stirred for 2 h at
room temperature. The solution was concentrated in vacuo, and the
residue was thoroughly dried under vacuum. The resulting unstable
amine hydrochloride was subsequently dissolved in dry degassed
DMF (15 mL) and 5,6,7-trimethoxyindole-2-carboxylic acid (TMI-
CO2H; 172 mg, 687 µmol) and 1-[3-(dimethylamino)propyl]-3-
ethylcarbodiimide hydrochloride (EDC) (131 mg, 687 µmol) were
added. The solution was stirred for 20 h at room temp. and poured
into brine (100 mL). The product was extracted with ethyl acetate,
washed with brine (200 mL) and dried with Na2SO4. Concentration
and purification by column chromatography (EtOAc/PE, 1:2) af-
forded 12 (70 mg, 116 µmol, 51%) as a light yellow solid.
Methyl (1R/S)-1-(Chloromethyl)-5-hydroxy-3-[(5,6,7-trimethoxyin-
dol-2-yl)carbonyl]-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carb-
oxylate (3)
1. Alkylation: Compound 9 (408 mg, 709 µmol) was dissolved in
Methyl (1R/S)-5-(Benzyloxy)-1-(chloromethyl)-3-[(5,6,7-trimethoxy-
DMF (15 mL) and treated with NaH (60% in oil, 51.1 mg, indole-2-yl)carbonyl]-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-
2.13 mmol). After stirring at room temperature for 30 min, 1,3-
dichloro-2-propene (157 mg, 1.42 mmol) was added. The mixture
was quenched with saturated aq. NH4Cl after 12 h at room temper-
carboxylate (11): IR (KBr): ν˜ ϭ 3462, 3300 (NϪH), 2925 (CϪH),
1713 (CϭO), 1526 (CϭC), 1492, 1440 (CH2, CH3) cmϪ1. UV
(CH3CN): λmax (lg ε) ϭ 208 (4.7), 236 (4.4), 304 (4.4), 332 (4.4)
1
ature. It was then extracted several times with ethyl acetate, and nm. H NMR (200 MHz, CDCl3): δ ϭ 3.59 (t, J ϭ 9.8 Hz, 1 H, 2-
the extracts were washed with water and brine and dried with
Ha), 3.90 (s, 3 H, OCH3), 3.92 (s, 6 H, 2ϫ OCH3), 4.07 (s, 3 H,
Eur. J. Org. Chem. 2003, 562Ϫ566
565

L. F. Tietze, F. Haunert, T. Feuerstein, T. Herzig
FULL PAPER
OCH3), 4.10 (m, 2 H, 1-H, 2-Hb), 4.58Ϫ4.78 (m, 2 H, 9-H2), 5.26
(s, 2 H, OCH2), 6.88 (s, 1 H, 4Ј-H), 6.98 (d, J ϭ 2.2 Hz, 1 H, 8-H),
7.15 (d, J ϭ 2.2 Hz, 1 H, 3Ј-H), 7.40Ϫ7.49 (m, 5 H, Ar-H), 8.19 (s,
1 H, 4-H), 9.17 (s, 1 H, NH), 9.43 (s, 1 H, NH) ppm. 13C NMR
(75.5 MHz, CDCl3): δ ϭ 43.6 (C-1), 46.5 (C-2), 52.2 (OCH3), 55.1
(C-9), 56.3 (OCH3), 61.1 (OCH3), 61.5 (OCH3), 70.6 (OCH2), 97.6
(C-4Ј), 98.5 (C-4), 105.8 (C-8), 106.3 (C-3Ј), 114.3 (C-6Ј), 123.5,
123.7, 125.4, 126.1, 128.1 (C-3aЈ, C-5a, C-7aЈ, C-8a, C-8b), 128.1,
128.12, 128.64 (Ar-CH), 130.1, 136.1, 138.7, 138.8, 140.4 (C-2Ј, C-
3a, C-5Ј, C-7, C-7Ј), 145.6 (Ar-C), 150.1 (C-5), 159.8 (NCϭO),
161.7 (CϭO) ppm. MS (70 eV, EI): m/z (%) ϭ 603 (100) [Mϩ].
Acknowledgments
This research was supported by the Deutsche Forschungsgemein-
schaft (Sonderforschungsbereich 416) and the Fonds der Chem-
ischen Industrie. F. H. thanks the Fonds der Chemischen Industrie
for a Ph.D. fellowship. Gifts of chemicals by BASF AG, Bayer AG,
Degussa AG, Dragoco Gerberding & Co. AG and Wacker-Chemie
GmbH are gratefully acknowledged.
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Methyl (1R/S)-1-(Chloromethyl)-5-hydroxy-3-[(5,6,7-trimethoxyin-
dol-2-yl)carbonyl]-1,2-dihydro-3H-pyrrolo[3,2-e]indole-7-carboxylate
(3): IR (KBr): ν˜ ϭ 3446 (NϪH, OϪH), 2936, 2836 (CϪH), 1718
(CϭO), 1587, 1527, 1494 (CϭC, CH2, CH3) cmϪ1. UV (CH3CN):
λmax (lg ε) ϭ 207 (3.0), 238 (4.3), 304 (4.5), 329 (4.4) nm. 1H NMR
(300 MHz, [D6]acetone): δ ϭ 3.85 (s, 3 H, OCH3), 3.86 (s, 3 H,
OCH3), 3.88 (m, 1 H, 9-Ha), 3.89 (s, 3 H, OCH3), 4.02 (s, 3 H,
OCH3), 4.13 (d, J ϭ 4.0 Hz, 1 H, 9-Hb), 4.17 (mc, 1 H, 1-H), 4.58
(dd, J ϭ 10.9, 4.0 Hz, 1 H, 2-Ha), 4.77 (m, 1 H, 2-Hb), 6.96 (d, J ϭ
8.3 Hz, 1 H, 4Ј-H), 7.05 (dd, J ϭ 8.3, 2.3 Hz, 1 H, 3Ј-H), 7.21 (s,
1 H, 8-H), 7.96 (s, 1 H, 4-H), 9.01 (br. s, 1 H, OH), 10.21 (br. s,
1 H, NH), 10.75 (br. s, 1 H, NH) ppm. 13C NMR (75.5 MHz,
[D6]acetone): δ ϭ 34.2 (C-1), 51.6 (OCH3), 55.7 (C-2), 55.9
(OCH3), 58.6 (C-9), 60.8 (OCH3), 60.9 (OCH3), 97.9 (C-4), 100.5
(C-4Ј), 105.4 (C-8), 105.8 (C-3Ј), 118.4 (C-5a), 123.1, 123.6, 124.9,
125.8, 127.6, 131.6, 136.6, 138.9, 139.5, 142.5, 148.9 (C-2Ј, C-3a,
C-3aЈ, C-5, C-5Ј, C-7, C-7Ј, C-7a, C-7aЈ, C-8a, C-8b), 159.4 (NCϭ
O), 161.3 (CϭO) ppm. MS (70 eV, EI): m/z (%) ϭ 513 (12) [Mϩ].
C25H24ClN3O7 (513.93): calcd. 513.1303; found 513.1302.
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Received August 2, 2002
[15]
[O02453]
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Eur. J. Org. Chem. 2003, 562Ϫ566