Synthesis of ring size seco-analogs of the antitumor antibiotic CC-1065 by two consecutive transition metal-initiated transformations

Article abstract of DOI:10.1002/ejoc.200300077

Novel seco-analogs of CC-1065 1 were synthesized from comercially available nitroaniline by reduction, bromination, bisulfonation and bisallylation followed by reaction with tert-butyllithium, zirconocene and iodine. The obtained quinoline 6 was then transformed into 17 and 18, which, upon treatment with Pd⁰, led to 21 and 22, respectively. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200300077

FULL PAPER
Synthesis of Ring Size seco-Analogs of the Antitumor Antibiotic CC-1065 by
Two Consecutive Transition Metal-Initiated Transformations
Lutz F. Tietze,*[a] Jan Looft,[a] and Tim Feuerstein[a]
Keywords: ADEPT / Antitumor agents / CC-1065 / Palladium / Zirconium
Novel seco-analogs of CC-1065 1 were synthesized from
comercially available nitroaniline by reduction, bromination,
bisulfonation and bisallylation followed by reaction with tert-
butyllithium, zirconocene and iodine. The obtained quinoline
6 was then transformed into 17 and 18, which, upon treat-
ment with Pd0, led to 21 and 22, respectively.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
nitrogen atoms using homoallylic iodide to afford 5 in 70%
yield over four steps (Scheme 2).
The chemotherapy of cancer is one of the major prob-
lems in modern medicine, since the known anticancer ag-
ents usually show severe side effects which often lead to a
termination of the treatment. A promising approach for
more selectivity is the antibody-directed enzyme prodrug
therapy (ADEPT),[1] which uses prodrugs in combination
with enzyme-immunoconjugates. A requirement for this ap-
proach is a relatively low toxicity of the prodrug, whereas
the corresponding drug, which is formed enzymatically
from the prodrug at the cancer cells, should have a high
cytotoxicity with an ED50 Յ 10 nmol.[2] Therefore appro-
priate derivatives of the highly cytotoxic antibiotic CC-1065
(1) such as the glycosidic seco-compound 2 are very suitable
candidates for ADEPT;[3Ϫ5] however we have recently
shown that the selectivity of the compounds differ strongly
with their structure.[6] It is therefore important to prepare
novel compounds for this approach.
Scheme 1. Synthesis of 5: a) PtO2/H2, dioxane, 18 h, 3 bar, quant.;
b) PhSO2Cl, pyridine, 3 h, 80 °C, 77%; c) NBS, THF, Ϫ78Ϫ20 °C,
95%, d) NaH, THF, 20 °C; 4-bromo-1-butene, nBu4NI, 50 °C, 93%
Here we describe the synthesis of two novel ring-size ana-
logs of the pharmacophoric group of CC-1065 by em-
ploying a combination of a zirconocene-mediated[7,8] and a
Pd0-catalyzed reaction.[9] This process allowed the synthesis
of compounds with a six-membered ring A and a six- as
well as a seven-membered ring C.
Results and Discussion
Scheme 2. Zirconocene-initiated cyclization of 5: a) Cp2ZrMeCl,
2 equiv. tBuLi, THF; b) 2 equiv. I2, CH2Cl2, 6: 45%, 7: 6%
Reduction[10] of the commercially available nitroaniline
3a, to give 3b, followed by formation of the bissulfonamide
3c and bromination led to 4, which was alkylated at the two
Treatment of 5 with two equivalents of tert-butyllithium
in THF at Ϫ78 °C, followed by reaction with chlorodi(cy-
clopentadienyl)methylzirconium {[Cp2ZrMeCl], 9}[11,12]
and finally two equivalents of iodine at 20 °C led to the
desired tetrahydroquinoline derivative 6 in 45% yield as the
main product (Scheme 3). In addition, 7% of the monoiodo
[a]
Institut für Organische Chemie der Georg August Universität
Göttingen,
Tammannstrasse 2, 37077 Göttingen, Germany
Fax: (internat.) ϩ49-(0)551Ϫ399476
E-mail: ltietze@gwdg.de
Eur. J. Org. Chem. 2003, 2749Ϫ2755
DOI: 10.1002/ejoc.200300077
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2749

L. F. Tietze, J. Looft, T. Feuerstein
FULL PAPER
Scheme 4. Synthesis of 16 and cyclization to give 6: a) NBS, THF,
Ϫ78Ϫ20 °C, 96%; b) hydrazine, FeCl3, charcoal, methanol, reflux,
99%; c) PhSO2Cl, pyridine, reflux, 80%; d) NaH, THF, 20 °C; 4-
bromo-1-butene, nBu4NI, 50 °C, 81%; d) Cp2ZrMeCl, 2 equiv.
tBuLi, THF; 2 equiv. I2, CH2Cl2, 6: 34%
However, steric interactions could also be responsible for
the high chemoselectivity by causing an unfavorable orien-
tation of the homoallylic group at the amino functionality
in the ortho-position to the methoxy group for the insertion
into the zircona species.
In order to prove that a zircona species of type 10 is an
intermediate, we synthesized the bromo compound 16 with
a meta-orientation of the bromo atom to the methoxy
group, which is available in four steps from 3a via 3dϪf in
a total yield of 61% (Scheme 5).
Scheme 3. Structure of model compound 13, the possible cycliza-
tion product 14 and intermediate 15
compound 7 was also obtained, which could not be re-
moved by chromatography at this stage.
Mechanistically, it can be assumed that an initial
halogenϪmetal exchange takes place to give the lithium
compound 8, which, upon reaction with [Cp2ZrMeCl] (9),
leads to the 16-electron Zr complex 10 and then, with loss
of methane, to the 14-electron complex 11. Insertion into
the homoallyl moiety meta to the methoxy group affords
the zircona-cyclopentene 12, which, upon reaction with iod-
ine, leads to compound 6. The formation of 7 could be ex-
plained by reaction of 12 with one mol of iodine and one
mol of water, which shows that the zirconoceneϪaryl bond
is cleaved first. A puzzling result in the formation of 6 from
the zirconacyclopropene moiety is the high regioselectivity,
Scheme 5. Formation of tetrahydroquinoline 17 and benzazepine
18 and Pd0-catalyzed cyclization of 19 and 20, respectively: a)
Ag2O·SiO2, H2O, 20 °C, 7 d, 83%, 17:18 ഠ1:1.7; b) Ac2O, NaOAc,
60 °C, 1 h, 96%; c) Pd(OAC)2, PPh3, Ag2CO3, DMF, 40 °C, 20 h,
83Ϫ85%
As expected, treatment of 16 with tert-butyllithium and
since only one of the two homoallylic groups in the ortho then zirconocene 9, and quenching the reaction with iodine,
positions in 11 undergoes a reaction. Clearly the selectivity also led to compound 6 as the only isolable product.
must be controlled by the methoxy group, though the zir-
A direct transformation of 6 into the desired pyrroloqui-
conocene-mediated reaction of 3-bromo-1-methoxybenzene noline skeleton by a palladium-catalyzed transformation
with acetonitrile leads to a 1:1 mixture of 2- and 3-meth- was not possible, since an oxidative addititon at the iodo-
oxyacetophenone, as described by Buchwald.[8]
methyl group also occurred, resulting in the formation of
Calculations of the 5-methoxy-N,NЈ-tetramethyl-1,4- 14. The iodomethyl group had therefore to be transformed
phenylenediamine (13) (Scheme 4) containing the proposed into an acetoxymethyl group. A simple substitution using
‘‘zirconacyclopropene’’ moiety using PM3TM (spartan) cesium acetate or tetrabutylammonium acetate was not
show a strongly deformed structure of the ‘‘zirconacyclo- suitable since an inseparable 1:1 mixture of the desired acet-
propene’’ moiety.[13] The CϪZr bond in the para-position ate 19 and the elimination product 14 was obtained
to the methoxy group is considerably longer (241 pm) than (Scheme 4). Reaction of 6 with DBU afforded 14 in nearly
the CϪZr bond in the meta-position (220 pm). This corre- quantitative yield. In order to avoid the elimination we used
lates with a different electron density at the aromatic ring silver oxide coated on silica gel for the transformation of 6
system: in the model compound the NBO charge at the to give the desired compound 17. However, rather unexpec-
carbon in the para-position to the methoxy group is tedly, the benzazepine 18 is the main product, which was
Ϫ0.08 eV, whereas the value in the meta-position is formed together with the expected tetrahydroquinoline 17
Ϫ0.34 eV.
in a 1.7:1 ratio in 75% overall yield. After acetylation, the
2750
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org Eur. J. Org. Chem. 2003, 2749Ϫ2755

Synthesis of Ring Size seco-Analogs of the Antitumor Antibiotic CC-1065
FULL PAPER
obtained two compounds 19 and 20, respectively, could be group in 20. The two diastereotopic hydrogens of the
separated by chromatography. The formation of the benza- CH2OAc group resonate at δ ϭ 3.42 ppm and δ ϭ
zepine derivative from 6 can be explained by assuming that
a spirocyclocyclohexadiene oxenium ion of type 15 acts as
3.89 ppm, whereas for the CHOAc group a multiplet at δ ϭ
4.89 ppm was observed. For the two hydrogens of the
an intermediate (Scheme 4). Attack of water of the silica gel methylene group of 21 and 22 two singlets at δ ϭ 4.94 and
at the secondary carbon of the spirocyclopropane moiety in 5.06 ppm, and at δ ϭ 4.80 and 5.10 ppm, respectively, were
15 would lead to 17, whereas an attack at the tertiary posi- found. The two hydrogens of the acetoxymethyl group in
tion would give 18. Interestingly, the reaction of CC-1065, 21 resonate at δ ϭ 3.64 ppm as a triplet with J ϭ 10.5 Hz
containing a spirocyclopropanecyclohexadienone moiety, and at δ ϭ 3.83 ppm as doublets of doublets with J ϭ 10.5,
with a nucleophile such as adenine takes place exclusively 4.0 Hz, respectively. For the hydrogen of the CHOAc group
at the secondary carbon atom of the cyclopropane moiety. of 22 a multiplet at δ ϭ 4.89 ppm was observed.
The final step in the synthesis of the new ring-size analogs
of the pharmacophoric group of CC-1065 was the Pd0-cata-
lyzed reaction of 19 and 20 to give 21 and 22, respectively
(Scheme 6). The best results with yields of 83Ϫ85% were
obtained using palladium acetate, silver carbonate as base,
and triphenylphosphane as ligand at 40 °C in DMF; under
these conditions an isomerization of the formed double
bond did not take place.[14Ϫ17]
Conclusion
A combination of a zirconocene-mediated and a Heck
reaction allowed the synthesis of novel ring-size seco-anal-
ogs of the pharmacophoric group of the highly cytotoxic
CC-1065. These compounds will be used for the synthesis
of new prodrugs for ADEPT.
Experimental Section
General: All reactions were performed in flame-dried glassware un-
der argon. Reagents obtained from commercial sources were used
without further purification. TLC chromatography was performed
on precoated aluminium silica gel SIL G/UV254 plates (Macherey,
Nagel Co.), and silica gel 32Ϫ63 (0.032Ϫ0.064 mm) (Macherey,
Nagel Co.) was used for column chromatography. (PE ϭ petroleum
ether, EA ϭ ethyl acetate). Melting points: Mettler FP61. IR: spec-
tra were recorded as KBr pellets or as films with a Bruker IFS 25
or Vector 22 spectrometer. NMR: Varian VXR-200 (200 MHz, 1H),
Bruker AM (300 MHz, 75 MHz, for 1H and 13C, respectively). For
1H and 13C NMR, CDCl3 as solvent, TMS as internal standard.
Chemical shifts are reported on the δ scale. Signals are quoted as
s (singlet), d (doublet), t (triplet), q (quadruplet), m (multiplet) and
br (broad). MS: Varian MAT 731. Elemental analysis: Mikroanaly-
tisches Labor des Instituts für Organische Chemie der Universität
Göttingen.
Scheme 6. Structure of the antitumor antibiotic CC-1065 (1) and
prodrug 2
The constitution of the new compounds was determined
by 1H and 13C NMR spectroscopy and for 18 a crystal
structure (Figure 1) was obtained.[18]
2-Methoxy-1,4-phenylenediamine (3b): A solution of 2-amino-5-
nitroanisole (3a, 22.1 g, 0.130 mmol) in 1,4-dioxane (170 mL) was
treated with PtO2·H2O (0.20 g, 0.80 mmol). The mixture was
placed under hydrogen (3 bar) and stirred for 16 h. After removal
of the catalyst by filtration through celite the solution was evapo-
rated to dryness. The diamine 3b was obtained as a pink solid and
was used in the next step without further purification. Rf ϭ 0.68
1
(PE/EA, 1:1); m.p. 101 °C. H NMR (200 MHz, [D6]DMSO): δ ϭ
3.24 (br s, 4 H, NH2), 3.80 (s, 3 H, OCH3), 6.19 (dd, J ϭ 2.2,
8.1 Hz, 1 H, 5-H), 6.27 (d, J ϭ 2.2 Hz, 1 H, 3-H), 6.57 (d, J ϭ
8.1 Hz, 1 H, 6-H) ppm. C7H10N2O (138.16).
2-Methoxy-N1,N4-bis(phenylsulfonyl)-1,4-phenylenediamine
(3c):
Benzenesulfonyl chloride (34 mL, 0.26 mol) was added dropwise
over 5 min to a solution of 3b in 300 mL of degassed pyridine and
the reaction mixture was heated at 80 °C for 3 h. After removal of
150 mL of the solvent, the solution was poured slowly into a 5%
HCl solution (500 mL). The formed solid was washed with water
and crystallized twice from ethyl acetate (250 mL) adding charcoal
to give 3c (44.2 g, 0.11 mol, 79%) as colorless crystals. Rf ϭ 0.12
Figure 1. X-ray structure of 18
The NMR spectra of 19 and 20 are very similar except
for the signals of the CH2OAC group in 18 and the CHOAc (EA/PE, 1:1); m.p. 208 °C. IR (KBr): ν˜ ϭ 3236 cmϪ1 (NϪH), 3098
Eur. J. Org. Chem. 2003, 2749Ϫ2755
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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L. F. Tietze, J. Looft, T. Feuerstein
FULL PAPER
(ArϪH), 1610 (CϭCAr), 1342 (SϭO), 1166 (CϪOϪC). UV 6-[3-Butenyl(phenylsulfonyl)amino]-5-iodo-7-methoxy-4-methyl-1-
1
(CH3CN): λmax (lg ε) ϭ 207.0 nm (4.596), 242.0 (4.037). H NMR phenylsulfonyl-1,2,3,4-tetrahydroquinoline (7): 1. A solution of tert-
(200 MHz, [D6]DMSO): δ ϭ 3.29 (s, 3 H, OCH3), 6.54 (d, J ϭ
butyllithium (1.70  in hexane) was added dropwise over 5 min
2.5 Hz, 1 H, 3-H), 6.58 (d, J ϭ 9.0 Hz, 1 H, 6-H), 7.04 (dd, J ϭ to a solution of 5 (4.00 g, 6.61 mmol) and [Cp2ZrCH3Cl] (1.90 g,
2.5, 9.0 Hz, 1 H, 5-H), 7.40Ϫ7.66 (m, 6 H, PhϪH), 7.67Ϫ7.76 (m,
4 H, PhϪH), 9.70 (br. s, 2 H, NϪH) ppm. 13C
7.30 mmol) in freshly distilled and degassed THF (50 mL) at Ϫ78
°C. The solution was stirred at Ϫ78 °C for 1 h, then warmed up to
NMR (50 MHz, [D6]DMSO): δ ϭ 55.1 (OCH3), 104.0 (C-3), 112.0 20 °C within 10 min and stirred at 40 °C for 5 h. After removal of
(C-5), 121.2 (C-1), 126.5 (C-Ph), 126.6 (C-Ph), 126.8 (C-6), 128.5 the solvent in vacuo, the residue was dissolved in dry, degassed
(C-Ph), 129.1 (C-Ph), 132.3 (C-Ph), 132.8 (C-Ph), 136.6 (C-4), CH2Cl2 and cooled to 0 °C. A solution of freshly sublimed iodine
139.3 (C-Ph), 140.4 (C-Ph), 153.2 (C-2) ppm. MS (70 eV): m/z
(3.50 g, 13.9 mmol) in CH2Cl2 (10 mL) was added over 15 min and
(%) ϭ 418 (13) [Mϩ], 277 (100) [Mϩ Ϫ SO2Ph], 141 (27) [SO2Phϩ], then the reaction mixture was stirred at 20 °C for 14 h. The solvent
77 (91) [C6H5ϩ], 43 (48) [C2H3Oϩ]. C19H18N2O5S2 (418.48): calcd.
C 54.53, H 4.34; found C 54.66, H 4.41.
was removed in vacuo and the residue was diluted with ethyl acet-
ate (100 mL). Na2SO3 (5.00 g, 39.7 mmol) was then added to re-
move the excess iodine and the resulting suspension stirred for 1 h.
After filtration of the solid, the filtrate was washed with brine, dried
with Na2SO4 and concentrated in vacuo. Chromatography (PE/EA,
2-Bromo-5-methoxy-N1,N4-bis(phenylsulfonyl)-1,4-phenylenedi-
amine (4): NBS (10.6 g, 59.7 mmol) was added to a solution of 3c
(25.0 g, 59.7 mmol) in 500 mL of THF at Ϫ78 °C and the solution
was stirred at Ϫ78 °C for 30 min. The reaction mixture was concen-
trated in vacuo and the residue was washed with water. Crystalliza-
5:1) gave the diiodo- and monoiodo compounds
6 (2.31 g,
2.97 mmol) and 7 (277 mg, 0.42 mmol) as an inseparable mixture
(7:1) in an overall yield of 51% as a colorless amorphous solid.
tion from glacial acetic acid (500 mL) yielded
7 (28.17 g,
56.64 mmol, 95%) as colorless crystals. Rf ϭ 0.27 (PE/EA, 3:1);
m.p.224 °C, IR (KBr): ν˜ ϭ 3248 cmϪ1 (NϪH), 3068 (ArϪH), 1602
(CϭC), 1344 (SϭO), 1160 (SϭO), 1042 (CϪOϪC). UV (CH3CN):
λmax (lg ε) ϭ 241 nm (4.425), 299.9 (4.579). 1H NMR
(200 MHz, [D6]DMSO): δ ϭ 3.31 (s, 3 H, OϪCH3), 6.59 (s, 1 H, 6-
H), 7.30 (s, 1 H, 3-H), 7.48Ϫ7.70 (m, 10 H, PhϪH) ppm. 13C NMR
(50 MHz, [D6]DMSO): δ ϭ 55.5 (OCH3), 109.9 (C-2), 111.1 (C-6),
124.9 (C-4), 126.5 (C-Ph), 126.7 (C-Ph), 128.2 (C-3), 128.8 (C-Ph),
129.0 (C-Ph), 132.7 (C-Ph), 132.8 (C-1), 140.4 (C-Ph), 151.6 (C-5)
2. Compound 13 (1.00 g, 1.65 mmol) was transformed as described
previously to 436 mg (0.56 mmol, 34%) of 6. Rf ϭ 0.20 (PE/EA,
4:1); m.p.70 °C. UV (CH3CN): λmax (lg ε) ϭ 232.0 nm (4.510),
303.5 (3.687). IR (KBr): ν˜ ϭ 3064 cmϪ1 (ArϪH), 2936 (CϪH),
1682 (CϭCchain), 1586 (CϭCcore), 1348 (SϭO), 1164 (SϭO).
1
6: H NMR (300 MHz, CDCl3): δ ϭ 1.65Ϫ1.80 (m, 2 H, 3-Ha, 3-
Hb), 1.95Ϫ2.13 (m, 1 H, 2Ј-Ha), 2.17 (dq, J ϭ 4.5, 14.0 Hz, 1 H, 4-
H), 2.29Ϫ2.45 (m, 1 H, 2Ј-Hb), 3.03 (dd, J ϭ 4.5, 10.0 Hz, 1 H, 1ЈЈ-
Ha), 3.13Ϫ3.25 (m, 1 H, 1ЈЈ-Hb), 3.21 (s, 3 H, OCH3), 3.37 (ddd,
J ϭ 5.3, 11.0, 13.5 Hz, 1 H, 1Ј-Ha), 3.42 (ddd, J ϭ 4.5, 13.0,
13.0 Hz, 1 H, 2-Ha), 3.75 (ddd, J ϭ 5.3, 11.0, 22.0 Hz, 1 H, 1Ј-Hb),
3.85 (ddd, J ϭ 3.8, 8.0, 13.0 Hz, 1 H, 2-Hb), 4.87Ϫ4.99 (m, 2 H,
CHϭCH2), 5.59 (mc, 1 H, CHϭCH2), 7.39Ϫ7.56 (m, 9 H, PhϪH,
8-H), 7.65Ϫ7.73 (m, 2 H, PhϪH) ppm. 13C NMR (50 MHz,
CDCl3): δ ϭ 6.8 (C-1ЈЈ), 25.9 (C-3), 32.9 (C-2Ј), 42.7 (C-1Ј), 44.3
(C-4), 49.5 (C-2), 55.1 (OCH3), 107.7 (C-8), 114.9 (C-5), 116.7
(CHϭCH2), 127.0, 127.9, 128.4 129.3 (C-2, C-3, C-5, C-6, 2 ϫ
SO2Ph), 127.2 (C-6), 127.5 (C-4a), 132.3, 134.9 (C-4, 2 ϫ SO2Ph),
133.6 (CHϭCH2), 137.6, 137.7 (C-1, 2 ϫ SO2Ph), 140.9 (C-8a),
155.7 (C-7) ppm. MS (70 ev): m/z (%) ϭ 778 (10) [Mϩ], 637 (100)
[M Ϫ SO2Phϩ], 596 (8) [M Ϫ SO2PHϪC3H5ϩ]. HRMS calcd. for
C27H28I2N2O5S2 777.9529; found 777.9529.
ppm. MS (70 eV): m/z (%) ϭ 497 (26) [Mϩ], 356 (100) [Mϩ
Ϫ
SO2Ph], 141 (38) [SO2Phϩ], 77 (72) [C6H5ϩ]. C19H17BrN2O5S2
(497.38): calcd. C 45.88, H 3.45; found C 46.08, H 3.48.
2-Bromo-N1,N4-bis(3-butenyl)-5-methoxy-N1,N4-bis(phenyl-
sulfonyl)-1,4-phenylenediamine (5):
A solution of 4 (5.00 g,
10.1 mmol) and NaH (603 mg, 25.1 mmol) in THF (100 mL) was
refluxed for 5 min. After cooling, 4-bromo-1-butene (3.39 g,
2.57 mL, 25.1 mmol) and nBu4NI (5.00 g, 13.5 mmol) were added
to the reaction mixture and the solution was refluxed for 24 h.
Water (20 mL) was added and the solvent was evaporated in vacuo.
The residue was diluted with ethyl acetate (50 mL), the organic
layer was washed three times with water (20 mL) as well as brine
and dried with Na2SO4. Removal of the solvent in vacuo and crys-
tallization from ethanol gave 5 (5.66 g, 9.35 mmol, 93%) as color-
less crystals. Rf ϭ 0.12 (PE/EA, 4:1); m.p.149 °C. IR (KBr): ν˜ ϭ
3072 cmϪ1 (ArϪH), 2944 (CϪH), 1696 (CϭCchain), 1592 (Cϭ
Ccore), 1348 (SϭO), 1164 (SϭO). UV (CH3CN): λmax (lg ε) ϭ
272.5 nm (3.523), 298.5 (3.656). 1H NMR (300 MHz, CDCl3): δ ϭ
2.22 (ddd, J ϭ 7.5, 7.5, 7.5 Hz, 2 H, 2Ј-Ha, 2Ј-Hb), 2.32 (ddd, J ϭ
7.5, 7.5, 7.5 Hz, 2 H, 2ЈЈ-Ha, 2ЈЈ-Hb), 3.26 (s, 3 H, OCH3),
3.54Ϫ3.82 (m, 4 H, 1Ј-Ha, 1Ј-Hb, 1ЈЈ-Ha, 1ЈЈ-Hb), 4.99Ϫ5.20 (m,
4 H, 2 ϫ CHϭCH2), 5.64Ϫ5.82 (m, 2 H, 2 ϫ CHϭCH2), 6.71 (s,
1 H, 6-H), 7.44Ϫ7.64 (m, 7 H, 3-H, PhϪH), 7.65Ϫ7.70 (m, 2 H,
PhϪH), 7.72Ϫ7.78 (m, 2 H, PhϪH) ppm. 13C NMR (125 MHz,
CDCl3): δ ϭ 33.4 (C-2ЈЈ), 33.5 (C-2Ј), 49.3 (C-1ЈЈ), 50.1 (C-1Ј), 55.4
(OCH3), 114.3 (C-2), 116.7 (C-6), 117.2, 117.4 (2 ϫ CHϭCH2),
127.5, 127.7, 128.5, 128.5 (C-2, C-3, C-5, C-6, 2 ϫ SO2Ph), 127.4
(C-4), 132.5, 133.0 (C-4, 2 ϫ SO2Ph), 134.6, 134.6 (2 ϫ CHϭCH2),
137.7 (C-3), 138.4 (C-1), 139.6. 136.9 (C-1, 2 ϫ SO2Ph), 155.8 (C-
5) ppm. MS (70 eV): m/z (%) ϭ 606 (14) [Mϩ], 565 (100) [M Ϫ
C3H5ϩ]. C27H29BrN2O5S2 (605.57): calcd. C 53.55, H 4.83; found
C 53.85, H 4.79.
7: 1H NMR (300 MHz, CDCl3): δ ϭ 0.94 (d, J ϭ 6.0 Hz, 3 H,
CH3), 1.16Ϫ1.28 (m, 1 H, 3-Ha), 1.60Ϫ1.76 (m, 1 H, 3-Hb), 2.40
(q, J ϭ 6.0 Hz, 2Ј-Ha, 2Ј-Hb), 2.50 (mc, 4-H), 3.30 (s, 3 H, OCH3),
3.52Ϫ3.94 (m, 4 H, 1Ј-Ha, 1Ј-Hb, 2-Ha, 2-Hb), 4.96Ϫ5.03 (m, 2 H,
CHϭCH2), 5.66Ϫ5.96 (m, 1 H, CHϭCH2), 7.04 (s, 1 H, 8-H),
7.40Ϫ7.70 (m, 8 H, PhϪH), 7.72Ϫ7.98 (m, 2 H, PhϪH) ppm.
2-Bromo-6-methoxy-4-nitroaniline (3d): NBS (22.2 g, 125 mmol)
was added to a solution of 2-amino-5-nitroanisole (3a, 20.0 g,
119 mmol) in THF (500 mL) at Ϫ78 °C and the reaction mixture
was stirred at Ϫ78 °C for 30 min and then at 20 °C for 2 h. The
solution was concentrated in vacuo and the residue was washed
with water. Crystallization of the crude product from glacial acetic
acid (100 mL) yielded 3d (28.2 g, 114 mmol, 96%) as red crystals.
Rf ϭ 0.38 (PE/EA, 2:1, VS: yellow); m.p.104 °C. UV (CH3CN):
λmax (lg ε) ϭ 194.5 nm (3.942), 262.0 (3.421), 375.0 (3.710). IR
(KBr): ν˜ ϭ 3502 cmϪ1 (NϪH), 3394 (NϪH), 1602 (Ar), 1502
(NO2), 1320 (NO2), 1284, 1234 (CϪOϪC). 1H NMR (200 MHz,
CDCl3): δ ϭ 3.98 (s, 3 H, OϪCH3), 4.95 (br. s, 2 H, NH2), 7.63 (d,
(4RS)-6-[3-Butenyl(phenylsulfonyl)amino]-5-iodo-4-iodomethyl-7- J ϭ 2.5 Hz, 1 H, 5-H), 8.10 (d, J ϭ 2.5 Hz, 1 H, 3-H) ppm. 13C
methoxy-1-phenylsulfonyl-1,2,3,4-tetrahydroquinoline (6) and (4RS)- NMR (50 MHz, [D6]DMSO): δ ϭ 56.3 (OϪCH3), 103.2 (C-6),
2752
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2749Ϫ2755

Synthesis of Ring Size seco-Analogs of the Antitumor Antibiotic CC-1065
104.5 (C-5), 121.7 (C-3), 135.8 (C-4), 143.0 (C-1), 145.0 (C-2) ppm. (C-5), 116.7, 117.5 (2 ϫ CHϭCH2), 124.0 (C-3), 126.8 (C-6), 127.6,
FULL PAPER
MS (70 eV): m/z (%) ϭ 264 (100) [Mϩ], 226 (34) [M Ϫ NH2؉], 216
127.8 (C-2Ј, C-6Ј, C-2ЈЈ, C-6ЈЈ), 128.3 (C-1), 128.5, 129.0 (C-3Ј, C-
(34), 200 (19) [M Ϫ NO2؉], 93 (37), 78 (80) [Brϩ], 51 (24) [C4H3؉]. 5Ј, C-3ЈЈ, C-5ЈЈ), 132.4 (C-4Ј), 133.1 (C-4ЈЈ), 134.1 (CHϭCH2),
C7H7BrN2O3 (247.04): calcd. C 34.03, H 2.86; found C 33.98, H 134.7 (CHϭCH2), 137.6 (C-4), 140.7 (C-1Ј, C-1ЈЈ), 158.2 (C-2)
2.89.
ppm. MS (70 eV): m/z (%) ϭ 606 (15) [Mϩ], 565 (69) [M Ϫ C3H5ϩ],
465 (100) [M Ϫ SO2Phϩ], 281 (75), 240 (83). C27H29BrN2O5S2
(605.56): calcd. C 53.85, H 4.79; found C 53.55, H 4.83.
2-Bromo-6-methoxy-1,4-phenylenediamine (3e): Hydrazine hydrate
(80%, 12.5 mL, 201 mmol) was added to a mixture of 3d (10.0 g,
40.5 mmol), charcoal (4.60 g, 383 mmol) and FeCl3·H2O (4.33 g,
1.60 mmol) in methanol and the solution was heated to reflux for
seven days. The reaction mixture was then diluted with ethyl acetate
(150 mL) and the solid filtered off. The organic layer was washed
four times with water (100 mL) and brine (100 mL) and dried with
Na2SO4. Removal of the solvent yielded 3e as a crimson solid
which was used in the next step without further purification due to
its sensitivity to oxygen.
6-[3-Butenyl(phenylsulfonyl)amino]-5-iodo-7-methoxy-4-methylene-
1-phenylsulfonyl-1,2,3,4-tetrahydroquinoline (14): 1,8-Diazabicy-
clo[5.4.0]undec-7-ene (58.6 mg, 57 µL, 0.385 mmol) was added to a
solution of 6 (300 mg, 0.385 mmol) in toluene (7.5 mL) and the
reaction mixture was stirred at 60 °C for 1.5 h. Removal of the
solvent in vacuo and chromatographic purification of the crude
product (2 ϫ 30 g SiO2, PE/EA, 2:1; 4:1) gave 14 as colorless
amorphous solid (228 mg, 0.35 mmol, 90%). Rf ϭ 0.5 (PE/EA, 1:1).
UV (CH3CN): λmax (lg ε) ϭ 220.0 nm (3.722), 302.5 (2.877).
IR (KBr): ν˜ ϭ 3061 cmϪ1 (ArϪH), 2963 (CϪH), 1734, 1639 (Cϭ
Cchain), 1587, 1445, 1355 (SϭO), 1250, 1168 (SϭO), 1090
1H NMR (200 MHz, CDCl3): δ ϭ 3.45 (br. s, 4 H, NH2), 3.80 (s,
3 H, OϪCH3), 6.19 (d, J ϭ 2.3 Hz, 1 H, 5-H), 6.46 (d, J ϭ 2.3 Hz,
1 H, 3-H) ppm.
1
(CϪOϪC), 1018, 923, 725, 694, 594. H NMR (300 MHz, C6D6):
δ ϭ 1.94 (t, J ϭ 7.4 Hz, 2 H, 3-H2), 2.40 (mc, 1 H, 2Ј-Ha), 2.67 (mc,
1 H, 2Ј-Hb), 2.86 (s, 3 H, OCH3), 3.40Ϫ3.51 (m, 2 H, 2-H2), 3.58
(ddd, J ϭ 5.5, 11.0, 13.5 Hz, 1 H, 1Ј-Ha), 3.98 (ddd, J ϭ 5.4, 12.0,
13.5 Hz, 1 H, 1Ј-Hb), 4.42 (s, 1 H, C4ϭCH2), 4.83Ϫ4.94 (m, 2 H,
HCϭCH2), 4.91 (s, 1 H, C4ϭCH2), 5.55 (mc, 1 H, HCϭCH2),
6.70Ϫ7.98 (m, 6 H, PhϪH), 7.40 (s, 1 H, 8-H), 7.41Ϫ7.48 (m, 2 H,
PhϪH), 7.76Ϫ7.80 (m, 2 H, PhϪH) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 22.9 (C-2Ј), 34.3 (C-3), 46.4 (C-1Ј), 49.7 (C-2), 55.2
(OCH3), 108.1 (C-5), 110.6 (C-8), 116.6 (C4ϭCH2), 117.5 (C-4Ј),
127.2, 127.8 (C-2, C-6, SO2Ph), 128.4, 128.8 (C-3, C-5, SO2Ph),
129.7 (C-4a), 132.2 (C-4, SO2Ph), 132.3 (C-6), 133.0 (C-4, SO2Ph),
134.9 (C-3Ј), 137.8 (C-8a), 138.6, 138.9 (C-1, SO2Ph), 140.9 (C-4),
156.1 (C-7) ppm. MS (70 eV): m/z (%) ϭ 650 (4) [Mϩ], 527 (10)
[Mϩ Ϫ I], 509 (25) [Mϩ Ϫ SO2Ph], 385 (59) [Mϩ Ϫ 2 ϫ SO2Ph],
203 (75), 162 (100), 147 (27) [SO2Phϩ], 77 (81) [C6H5ϩ]. HRMS
calcd. for C27H27IN2O5S2: 650.0406; found 650.0406.
C27H27IN2O5S2 650.54): calcd. C 49.85, H 4.18; found C 50.11,
H 4.11.
2-Bromo-6-methoxy-N1,N4-bis(phenylsulfonyl)-1,4-phenylene-
diamine (3f): Benzenesulfonyl chloride (14.0 g, 79.4 mmol) was ad-
ded dropwise to a solution of 3e (8.61 g, 39.7 mmol) in dry, de-
gassed pyridine (300 mL) and the solution was refluxed for 3 h.
The reaction mixture was reduced in vacuo to 100 mL and the re-
sulting black oil was poured into an ice cooled HCl solution
(500 mL, 5% HCl). Removal of the solid and crystallization from
glacial acetic acid gave 3f as colorless crystals (16.0 g, 32.2 mmol,
81%). Rf ϭ 0.08 (PE/EA, 2:1); m.p. 208.5 °C (dec.). UV (CH3CN):
λmax (lg ε) ϭ 213.0 nm (3.928), 292.5 (2.961), 272.0 (3.038). IR
(KBr): ν˜ ϭ 3252 cm-1 (NϪH), 1596 (Ar), 1384 (SϭO), 1322
(CϪN), 1166 (CϪOϪC), 1044 (ArϪBr). 1H NMR (200 MHz,
CDCl3): δ ϭ 3.41 (s, 3 H, OCH3), 6.13 (br. s, 1 H, NϪH), 6.53 (br.
s, 1 H, NϪH), 6.66 (d, J ϭ 2.5 Hz, 1 H, 5-H). 6.77 (d, J ϭ 2.5 Hz,
1 H, 3-H), 7.40Ϫ7.66 (m, 8 H, PhϪH), 7.70Ϫ7.83 (m, 2 H, PhϪH)
ppm. 13C NMR (50 MHz, [D6]DMSO): δ ϭ 55.1 (OCH3), 102.0
(C-5), 114.4 (C-3), 119.6 (C-6), 126.1 (C-1), 126.4 (C-2Ј, C-6Ј),
126.7 (C-2ЈЈ, C-6ЈЈ), 128.4 (C-3Ј, C-5Ј), 129.4 (C-3ЈЈ, C-5ЈЈ), 132.0
(C-4Ј), 133.3 (C-4ЈЈЈ), 138.7 (C-4), 139.0 (C-1Ј), 142.2 (C-1ЈЈ), 157.3
(C-2) ppm. MS (70 eV): m/z (%) ϭ 496 (8.0) [Mϩ], 355 (100) [M Ϫ
SO2Phϩ], 215 (25) [M Ϫ 2 ϫ SO2Phϩ], 141 (21) [SO2Phϩ], 77 (33)
[C6H5ϩ]. C19H17BrN2O5S2 (497.38): calcd. C 45.88, H 3.44; found
C 46.19, H 3.62.
(4RS)-6-[3-Butenyl(phenylsulfonyl)amino]-4-hydroxymethyl-5-iodo-
7-methoxy-1-phenylsulfonyl-1,2,3,4-tetrahydroquinoline (17) and
(4RS)-7-[3-Butenyl(phenylsulfonyl)amino]-4-hydroxymethyl-6-iodo-
8-methoxy-1-phenylsulfonyl-2,3,4,5-tetrahydrobenzazepine (18):
A
suspension of silver oxide (1.04 g, 4.49 mmol) and silica gel (3.56 g)
in acetone (15 mL) was evaporated in vacuo until dryness, the resi-
due was dissolved in a mixture of acetone (15 mL), 14 (1.74 g,
2.24 mmol), and water (0.15 mL, 8.33 mmol), and stirred at 20 °C
for 7 d. Removal of the solvent in vacuo and flash chromatography
of the resulting solid yielded 1.24 g (83%) of a mixture (1:1.7) of
tetrahydroquinoline 17 and tetrahydrobenzazepine 18 which could
be separated by column chromatography (EA). However, a separ-
ation after acetylation to give 19 and 20 is more appropriate (PE/
EA, 2:1).
2-Bromo-N1,N4-bis(3-butenyl)-6-methoxy-N1,N4-bis(phenyl-
sulfonyl)-1,4-phenylenediamine (16):
A solution of 3f (2.00 g,
4.02 mmol) and NaH (193 mg, 8.04 mmol) in THF (100 mL) was
refluxed for 5 min. After cooling, 4-bromo-1-butene (0.41 mL,
4.02 mmol) and nBu4NI (20 mg) were added and the reaction mix-
ture was heated under reflux for 24 h. Water (20 mL) was then ad-
ded and the organic solvent was evaporated in vacuo. The residue
was diluted with ethyl acetate (50 mL), the organic layer washed
three times with water (20 mL) as well as brine and dried over
Na2SO4. Removal of the solvent in vacuo and crystallization of the
(4RS)-7-[3-Butenyl(phenylsulfonyl)amino]-4-hydroxymethyl-6-iodo-
residue from ethanol gave 16 (1.97 g, 3.26 mmol, 81%) as colorless 8-methoxy-1-phenylsulfonyl-2,3,4,5-tetrahydrobenzazepine
crystals. Rf ϭ 0.20 (PE/EA, 2:1); m.p. 130.5 °C. UV (CH3CN): Rf ϭ 0.083 (EA). UV (CH3CN): λmax (lg ε) ϭ 219.0 nm (4.536),
λmax (lg ε) ϭ 293.5 nm (2.870), 272.0 (2.890). IR (KBr): ν˜ ϭ 3084
303.0 (3.706). IR (KBr): ν˜ ϭ 3448 cmϪ1 (OH), 3066 (ArϪH), 2964
cmϪ1 (ArϪH), 1642 (CϭC), 1447 (CϪH), 1351 (SϭO), 1167 (Sϭ (CϪH), 1638 (CϭCchain), 1586 (CϭCAr), 1348 (SϭO), 1164 (Sϭ
(18):
1
1
O), 1042 (CϪOϪC). H NMR (200 MHz, CDCl3): δ ϭ 2.07Ϫ2.51 O), 1090 (CϪOϪC). H NMR (200 MHz, CDCl3): δ ϭ 1.68Ϫ2.00
(m, 4 H, 2 ϫ CH2), 3.3.34 (s, 3 H, OCH3), 3.36Ϫ3.84 (m, 4 H, 2 ϫ (m, 2 H, 3-H2), 2.10Ϫ2.33 (m, 1 H, 2Ј-Ha), 2.35Ϫ2.59 (m, 1 H, 2Ј-
CH2), 4.95Ϫ5.15 (m, 4 H, 2 ϫ CHϭCH2), 5.72 (mc, 2 H, 2 ϫ CHϭ
Hb), 2.80Ϫ3.08 (m, 2 H, 5-H2), 3.22 (s, 3 H, OCH3), 3.42 (ddd, J ϭ
CH2), 6.81 (s, 2 H, 3-H, 5-H), 7.45Ϫ7.70 (m, 8 H, PhϪH), 5.6, 11.2, 13.5 Hz, 1 H, 1Ј-Ha), 3.52Ϫ3.80 (m, 1 H, 2-Ha), 3.77
7.77Ϫ7.86 (m, 2 H, PhϪH) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ (ddd, J ϭ 5.6, 11.0, 13.5 Hz, 1 H, 1Ј-Hb), 3.81Ϫ4.02 (m, 2 H, 2-
32.8, 33.2 (2 ϫ CH2), 49.5, 49.9 (2 ϫ CH2), 55.5 (OCH3), 113.0
www.eurjoc.org
Hb, 4-H), 4.95Ϫ5.09 (m, 2 H, CHϭCH2), 5.68 (mc, 1 H, CHϭ
2753
Eur. J. Org. Chem. 2003, 2749Ϫ2755
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

L. F. Tietze, J. Looft, T. Feuerstein
FULL PAPER
CH2), 6.82 (s, 1 H, 9-H), 7.42Ϫ7.68 (m, 6 H, PhϪH), 7.75Ϫ7.81 1, C-6, 2 ϫ SO2Ph), 132.2 (CHϭCH2), 133.6, 134.8 (C-4, 2 ϫ
(m, 4 H, PhϪH) ppm. 13C NMR (125 MHz, CDCl3): δ ϭ 29.7 (C- SO2Ph), 137.9, 138.5 (C-1, 2 ϫ SO2Ph), 140.9 (C-8a), 155.5 (C-7),
5), 33.1 (C-2Ј), 35.4 (C-3), 46.1 (C-2), 49.9 (C-1), 55.1 (OCH3), 65.8
170.5 (CϭO) ppm. MS (70 ev): m/z (%) ϭ 710 (11), [Mϩ], 569 (100)
(C-4), 113.0 (C-9), 116.8 (CHϭCH2), 127.1, 127.9 (C-2, C-5, 2 ϫ [Mϩ Ϫ SO2Ph], 528 (8) [Mϩ Ϫ SO2Ph Ϫ CH3CO], 429 (13), 327
SO2Ph), 128.5, 129.3 (C-1, C-6, 2 ϫ SO2Ph), 130.5 (C-5a), 132.3 (18). HRMS calcd. for C29H31IN2O7S2 710.0617; found 710.0617
(C-4, SO2Ph), 132.7 (C-7), 133.1 (C-4, SO2Ph), 134.9 (CHϭCH2), (MS). C29H31IN2O7S2 (710.59): calcd. C 49.02, H 4.40; found C
139.9 (C-9a), 140.8, 141.0 (C-1, 2 ϫ SO2Ph), 155.6 (C-8) ppm. MS 49.15, H 4.33.
(70 ev): m/z (%) ϭ 668 (11) [Mϩ], 527 (100) [Mϩ Ϫ SO2Ph], 486
(10) [Mϩ Ϫ C3H5ϪSO2Ph], 77 (44) [C6H5ϩ], 69 (74) [C4H5Oϩ].
HRMS calcd. for C27H29IN2O6S2: 668.0511; found 668.0511.
C27H29IN2O6S2 (668.57): calcd. C 48.51, H 4.37; found C 48.36,
H 4.37.
(4RS)-4-Acetoxymethyl-7-[3-butenyl(phenylsulfonyl)amino]-6-iodo-
8-methoxy-1-phenylsulfonyl-2,3,4,5-tetrahydrobenzazepine (20):
A
solution of 18 (558 mg, 0.84 mmol) and sodium acetate (83.5 mg,
1.02 mmol) in acetic anhydride (6 mL) was stirred at 60 °C for 1 h.
The reaction mixture was diluted with toluene (100 mL) and the
solvents were removed in vacuo. The residue was dissolved in ethyl
acetate (50 mL), and the organic layer was washed twice with water
(4RS)-6-[3-Butenyl(phenylsulfonyl)amino]-4-hydroxymethyl-5-iodo-
7-methoxy-1-phenylsulfonyl-1,2,3,4-tetrahydroquinoline (17): Rf
ϭ
0.125 (EA). UV (CH3CN): λmax (lg ε) ϭ 217.0 nm (4.614), 292.0 (10 mL) and brine, dried with Na2SO4 and the solvent was removed
(3.782), 300.0 (3.776). IR (KBr): ν˜ ϭ 3438 cmϪ1 (OH), 3068
in vacuo. Purification by column chromatography (50 g SiO2, PE/
(ArϪH), 2926 (CϪH), 1640 (CϭCchain), 1586 (CϭCAr), 1346 (Sϭ EA, 2:1) furnished 20 (572 mg, 0.805 mmol, 96%) as a colorless
O), 1162 (SϭO), 1088 (CϪOϪC). 1H NMR (300 MHz, CDCl3): solid. Rf ϭ 0.23 (PE/EA, 2:1). UV (CH3CN): λmax (lg ε) ϭ
δ ϭ 1.62Ϫ1.77 (m, 1 H, 3-Ha), 2.07Ϫ2.27 (m, 2 H, 3-Hb, 2Ј-Ha),
2.37Ϫ2.52 (m, 1 H, 2Ј-Hb), 2.72 (mc, 1 H, 4-H), 3.18 (mc, 1 H, 1ЈЈ-
218.5 nm (3.729), 301.0 (2.788). IR (KBr): ν˜ ϭ 3068 cmϪ1
(ArϪH), 2940 (CϪH), 1738 (CϭO), 1586 (CϭC), 1444, 1348 (Sϭ
Ha), 3.28 (s, 3 H, OCH3), 3.43 (ddd, J ϭ 5.5, 10.5, 13.0 Hz, 1 H, O), 1244, 1164 (CϪOϪC). 1H NMR (300 MHz, C2D2Cl4, 100 °C):
1Ј-Ha), 3.55 (mc, 1 H, 1ЈЈ-Hb), 3.67 (dt, J ϭ 4.5, 12.0 Hz, 1 H, 2-
δ ϭ 1.75Ϫ1.85 (m, 1 H, 3-Ha), 1.92 (s, 3 H, CH3COO), 1.92Ϫ2.05
Ha), 3.81 (ddd, J ϭ 5.5, 11.0, 13.0 Hz, 1Ј-Hb), 3.97 (ddd, J ϭ 4.0, (m, 1 H, 3-Hb), 2.11Ϫ2.28 (m, 1 H, 2Ј-Ha), 2.29Ϫ2.45 (m, 1 H, 2Ј-
6.0, 12.0 Hz, 1 H, 2-Hb), 4.93Ϫ5.04 (m, 2 H, CHϭCH2), 5.66 (mc, Hb), 2.94 (dd, J ϭ 3.0, 14.5 Hz, 1 H, 5-Ha), 3.11 (dd, J ϭ 8.0,
1 H, CHϭCH2), 7.42Ϫ7.66 (m, 9 H, PhϪH, 8-H), 7.74Ϫ7.81 (m,
14.5 Hz, 1 H, 5-Hb), 3.28 (s, 3 H, OCH3), 3.48 (ddd, J ϭ 5.7, 10.0,
2 H, PhϪH) ppm. 13C NMR (125 MHz, CDCl3): δ ϭ 22.9 (C-2Ј), 14.5 Hz, 1 H, 1Ј-Ha), 3.67Ϫ3.80 (m, 3 H, 1Ј-Hb, 2-H2), 4.91Ϫ5.00
33.0 (C-3), 43.4 (C-1Ј), 44.6 (C-4), 49.7 (C-2), 55.0 (OCH3), 62.7 (m, 3 H, 4-H, CHϭCH2), 5.66 (mc, 1 H, CHϭCH2), 6.77 (s, 1 H,
(4-CH2), 107.4 (C-8), 115.3 (C-5), 116.7 (CϭCH2), 125.7 (C-4a), 9-H), 7.43Ϫ7.63 (m, 6 H, SO2Ph), 7.74Ϫ7.80 (m, 4 H, SO2Ph)
127.1 (C-2, C-6, SO2Ph), 127.3 (C-6), 127.9 (C-2, C-6, SO2Ph),
ppm. 13C NMR (75 MHz, C2D2Cl4, 100 °C): δ ϭ 20.7 (CH3COO),
128.5, 129.2 (C-3, C-5, 2 ϫ SO2Ph), 132.3, 133.5 (C-4, 2 ϫ SO2Ph), 32.0 (C-5), 32.4 (C-2Ј), 42.1 (C-3), 45.7 (C-2), 49.7 (C-1Ј), 54.9
135.0 (CHϭCH2), 138.3, 138.4 (C-1, 2 ϫ SO2Ph), 141.0 (C-8a), (OCH3), 67.2 (C-4), 112.8 (C-9), 114.3 (C-6), 116.2 (C-4Ј), 126.8,
155.3 (C-7) ppm. MS (70 ev): m/z (%) ϭ 668 (24) [Mϩ], 627 (98) 127.7, 128.1. 129.0 (C-2, C-3, C-5, C-6, 2 ϫ SO2Ph), 130.9 (C-5a),
[Mϩ Ϫ C3H5], 527 (100) [Mϩ Ϫ SO2Ph], 486 (10) [Mϩ Ϫ C3H5 Ϫ 131.97 (C-4, SO2Ph), 132.4 (C-7), 132.8 (C-4, SO2Ph), 134.8 (C-3Ј),
SO2Ph], 347 (32) [Mϩ Ϫ 2 ϫ SO2Ph Ϫ C3H5], 77 (23) [C6H5ϩ].
139.2 (C-9a), 140.6, 141.1 (C-1, 2 ϫ SO2Ph), 156.0 (C-8), 169.3
HRMS calcd. for C27H29IN2O6S2 668.0511; found 668.0511. (CϭO) ppm. MS (70 eV): m/z (%) ϭ 710 (18) [Mϩ], 669 (100) [Mϩ
C27H29IN2O6S2 (668.56): calcd. C 48.51, H 4.37; found C 48.60,
H 4.42.
Ϫ CH3CO], 569 (100) [Mϩ Ϫ SO2Ph], 528 (30) [Mϩ Ϫ SO2Ph Ϫ
CH3CO], 327 (61). HRMS calcd. for C29H31IN2O7S2 710.0617;
found 710.0617. C29H31IN2O7S2 (710.59): calcd. C 49.02, H 4.40;
found C 48.93, H 4.21.
(4RS)-4-Acetoxymethyl-6-[3-butenyl(phenylsulfonyl)amino]-5-iodo-
7-methoxy-1-phenylsulfonyl-1,2,3,4-tetrahydroquinoline (19):
A
solution of 17 (495 mg, 0.740 mmol) and sodium acetate (74.5 mg,
0.908 mmol) in acetic anhydride (5 mL) was stirred at 60 °C for
(1RS)-1-Acetoxymethyl-6-methoxy-10-methylene-4,7-bis(phenyl-
sulfonyl)-1,2,3,4,7,8,9,10-octahydropyridino[3,2-f]quinoline (21): A
1 h. The reaction mixture was diluted with toluene (80 mL) and the mixture of palladium acetate (6.70 mg, 29.8 µmol) and tri-
solvents were removed in vacuo. The residue was dissolved with
ethyl acetate (50 mL), and the organic layer was washed twice with
water (10 mL) and brine, dried with Na2SO4 and the solvents were
removed in vacuo. Purification by column chromatography (50 g
SiO2, PE/EA, 2:1) furnished 19 (506 mg, 0.712 mmol, 96%) as a
phenylphosphane (15.4 mg, 58.7 µmol) in degassed DMF (5 mL)
was stirred at 20 °C for 5 min. Silver carbonate (78.5 mg, 285 µmol)
and a solution of 19 (100 mg, 140 µmol) in DMF (1 mL) were
added and the reaction mixture was heated at 60 °C for 20 h. The
mixture was diluted with ethyl acetate, filtered through a short col-
colorless solid. Rf ϭ 0.30 (PE/EA, 2:1). UV (CH3CN): λmax (lg ε) ϭ umn with layers of SiO2/Celite/charcoal/Celite/SiO2, washed twice
219.5 nm (3.740), 302.0 (2.884), 295.0 (2.861). IR (KBr): ν˜ ϭ
with water and brine, dried with Na2SO4 and the solvent was re-
moved in vacuo and the residue purified by column chromatogra-
3900 cmϪ1, 3444, 2856 (CϪH), 1736 (CϭO), 1352 (SϭO), 1248,
1
1168 (SϭO), 1090 (CϪOϪC), 592. H NMR (200 MHz, CDCl3): phy (15 g SiO2, PE/EA, 3:1) to yield 21 (70.0 mg, 120 µmol, 85%) as
δ ϭ 1.66Ϫ1.84 (m, 1 H, 3-Ha), 1.90Ϫ2.25 (m, 2 H, 3-Hb, 2Ј-Ha),
colorless amorphous solid. Rf ϭ 0.44 (PE/EA, 2:1). UV (CH3CN):
2.04 (s, 3 H, CH3COO), 2.30Ϫ2.55 (m, 1 H, 2Ј-Hb), 3.19 (mc, 1 H, λmax (lg ε) ϭ 220.0 nm (3.687). IR (KBr): ν˜ ϭ 3446 cmϪ1, 3420,
4-H), 3.28 (s, 3 H, OCH3), 3.33Ϫ3.50 (m, 2 H, 1Ј-Ha, 1ЈЈ-Ha), 3.65 1738 (CϭO), 1588 (CϭCAr), 1476, 1446, 1352 (SϭO), 1232, 1164
1
(dt, J ϭ 4.7, 13.0 Hz, 1 H, 2-Ha), 3.72Ϫ3.89 (m, 2 H, 1ЈЈ-Hb, 1Ј-
(SϭO), 1090 (CϪOϪC), 1036, 752 598, 580. H NMR (300 MHz,
Hb), 3.96 (ddd, J ϭ 3.0, 6.0, 13.0 Hz, 1 H, 2-Hb), 4.92Ϫ5.09 (m, C6D6, 50 °C): δ ϭ 1.23Ϫ1.38 (m, 2 H, 2-H2), 1.56 (s, 3 H,
2 H, CHϭCH2), 5.66 (mc, 1 H, CHϭCH2), 7.42Ϫ7.68 (m, 9 H, CH3COO), 2.20Ϫ2.32 (m, 1 H, 9-Ha), 2.37Ϫ2.51 (m, 1 H, 9-Hb),
PhϪH, 8-H), 7.73Ϫ7.83 (m, 2 H, PhϪH) ppm. 13C NMR
3.06Ϫ3.20 (m, 1 H, 8-Ha), 3.27Ϫ3.36 (m, 1 H, 1-H), 3.43 (t, J ϭ
(50 MHz, CDCl3): δ ϭ 20.8 (CH3COO), 23.3 (C-2Ј), 32.9 (C-3), 10.5 Hz, 1 H, ϪCHaϪO), 3.50 (s, 3 H, OCH3), 3.58Ϫ3.73 (m, 2 H,
41.4 (C-4), 43.1 (C-1), 49.6 (C-2), 54.9 (OCH3), 62.9 (C-1Ј), 107.3 3-H2), 3.66 (dd, J ϭ 10.5, 4.0 Hz, 1 H, ϪCHbϪO), 3.81 (dd, J ϭ
(C-8), 115.1 (C-5), 116.7 (CHϭCH2), 124.8 (C-4a), 127.0 (C-2, C-
13.2, 4.5, 4.5 Hz, 1 H, 8-Hb), 4.68 (s, 1 H, CϭCH2), 4.76 (s, 1 H,
5, SO2Ph), 127.2 (C-6), 127.8 (C-2, C-5, SO2Ph), 128.4, 129.2 (C- CϭCH2), 6.88Ϫ7.04 (m, 7 H, PhϪH, 5-H), 7.61Ϫ7.67 (m, 2 H,
2754
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2003, 2749Ϫ2755

Synthesis of Ring Size seco-Analogs of the Antitumor Antibiotic CC-1065
FULL PAPER
PhϪH), 7.68Ϫ7.76 (m, 2 H, PhϪH) ppm. 1H NMR (300 MHz, MS (70 eV): m/z (%) ϭ 582 (7) [Mϩ], 441 (100) [Mϩ Ϫ SO2Ph], 381
C2D2Cl4, 120 °C): δ ϭ 1.69Ϫ1.83 (m, 1 H, 2-Ha), 1.92Ϫ2.03 (m, (3) [Mϩ Ϫ SO2Ph Ϫ CH3COO], 301 (12) [Mϩ Ϫ 2 ϫ SO2Ph], 241
1 H, 2-Hb),1.97 (s, 3 H, CH3COO), 2.68 (ddd, J ϭ 3.5, 7.0, 14.0 Hz, (12) [Mϩ Ϫ 2 ϫ SO2Ph Ϫ CH3COO], 77 (10) [C6H5ϩ]. HRMS
1 H, 9-Ha), 2.82 (dt, J ϭ 7.0, 14.0 Hz, 1 H, 9-Hb), 3.51 (ddd, J ϭ
5.5, 9.0, 16.0 Hz, 1 H, 8-Ha), 3.54Ϫ3.60 (m, 1 H, 1-H), 3.64 (t, J ϭ
10.5 Hz, 1 H, 1-CHaϪ), 3.78 (s, 3 H, OCH3), 3.83 (dd, J ϭ 4.0,
10.5 Hz, 1 H, 1-CHbϪ), 3.85Ϫ3.98 (m, 3 H, 3-H, 8-Hb), 4.94 (s,
1 H, CϭCH2), 5.06 (s, 1 H, CϭCH2), 7.41 (s, 1 H, 5-H), 7.42Ϫ7.65
(m, 6 H, PhϪH), 7.70Ϫ7.79 (m, 2 H, PhϪH), 7.80Ϫ7.89 (m, 2 H,
PhϪH) ppm. 13C NMR (300 MHz, C2D2Cl4, 100 °C): δ ϭ 20.3
(CH3COO), 24.1 (C-2), 31.4 (C-1), 36.1 (C-9), 43.1 (C-3), 45.4 (C-
8), 55.7 (OCH3), 65.1 (C-1Ј), 108.1 (C-5), 116.2 (CϭCH2), 118.2
(C-10b), 124.8 (C-6a), 126.9, 127.3 (C-3, C-5, 2 ϫ SO2Ph), 128.2,
128.9 (C-2, C-6, 2 ϫ SO2Ph), 132.0, 132.8 (C-4, 2 ϫ SO2Ph), 136.9
(C-10a), 137.3 (C-4a), 138.2, 139.5 (C-1, 2 ϫ SO2Ph), 141.24 (C-
6), 153.8 (C-10), 169.9 (CϭO) ppm. MS (70 eV): m/z (%) ϭ 582 (6)
[Mϩ], 441 (100) [Mϩ Ϫ SO2Ph], 301 (15) [Mϩ Ϫ2 ϫ SO2Ph], 91
(11) [C7H7ϩ], 77 (8) [C6H6ϩ]. HRMS calcd. for C29H30N2O7S2
582.1494; found 582.1494. C29H30N2O7S2 (582.68): calcd. C 59.78,
H 5.19; found C 60.06, H 5.28.
calcd. for C29H30N2O7S2: 582.1494, found 582.1494.
Acknowledgments
This work was supported by the Deutsche Forschungsgemeinschaft
(SFB, 416) and the Fonds der Chemischen Industrie. We are also
indebted to the BASF AG, the Bayer AG, the Degussa AG, the
Dragoco Gerberding & Co. AG, Wacker-Chemie GmbH for
generous gifts of chemicals.
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(2RS)-2-Acetoxy-7-methoxy-11-methylene-5,8-bis(phenylsulfonyl)-
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of palladium acetate (6.70 mg, 29.8 µmol) and triphenylphosphane
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dried with Na2SO4 and the solvent was removed in vacuo and the
residue purified by column chromatography (15 g SiO2, PE/EA,
3:1) to yield 22 (68.5 mg, 118 µmol, 84%) as a colorless amorphous
solid. Rf ϭ 0.32 (PE/EA, 2:1); m.p. 70 °C. UV (CH3CN):
λmax (lg ε) ϭ 225.5 nm (2.729), 300.0 (1.791). IR (KBr): ν˜ ϭ 3434
cmϪ1, 2934 (CϪH), 1736 (CϭO), 1446, 1342 (SϭO), 1244, 1224,
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1
1162 (SϭO), 1092 (CϪOϪC), 692, 578 ppm. H NMR (300 MHz,
(USA), 1995.
C2D2Cl4, 120 °C): δ ϭ 1.98 (s, 3 H, CH3COO), 2.01Ϫ2.13 (m, 2 H,
3-H2), 2.62Ϫ2.80 (m, 2 H, 10-H2), 2.91 (d, J ϭ 6.0 Hz, 2 H, 1-H2),
3.53Ϫ3.70 (m, 2 H, 4-Ha, 9-Ha), 3.64 (s, 3 H, OCH3), 3.82 (ddd,
J ϭ 5.0, 9.0, 14.0 Hz, 1 H, 4-Hb), 4.01 (ddd, J ϭ 4.5, 6.5, 14.0 Hz,
1 H, 9-Hb), 4.84Ϫ4.94 (m, 1 H, 2-H), 4.88 (s, 1 H, CϭCH2), 5.10
(s, 1 H, CϭCH2), 6.77 (s, 1 H, 6-H), 7.42Ϫ7.67 (m, 6 H, PhϪH),
7.83Ϫ7.93 (m, 4 H, PhϪH) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ
21.2 (CH3COO), 33.2Ϫ33.8 (C-1), 34.4 (C-3), 35.3 (C-10), 45.2 (C-
4), 46.9 (C-9), 55.6 (OCH3), 69.2Ϫ69.9 (C-2), 111.6 (C-6), 118.2
(CϭCH2), 124.4 (C-11b), 127.0 (C-7a), 127.1, 127.7 (C-2, C-6, 2 ϫ
SO2Ph), 128.6, 129.1 (C-3, C-5, 2 ϫ SO2Ph), 132.5, 132.9 (C-4, 2
ϫ SO2Ph), 136.6 (C-11a), 139.5 (C-5a), 140.4, 141.0 (C-1, 2 ϫ
SO2Ph), 141.4 (C-7), 153.6 (C-11), 170.0 (CϭO) ppm.
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CCDC-196903 (18) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/conts/retrieving.html (or from
the Cambridge Crystallographic Data Center, 12 Union Road,
Cambridge CB21EZ, UK; fax (internat.) ϩ44-1223/336-033;
or deposit@ccdc.cam.uk).
Received February 7, 2003
Eur. J. Org. Chem. 2003, 2749Ϫ2755
www.eurjoc.org
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2755