First synthesis of pyrrolo[1,2:1′,2′]azepino[5,6-b]indole derivatives

Article abstract of DOI:10.1016/S0040-4039(03)01703-9

A new family of pyrrolo[1,2:1′,2′]azepino[5,6-b]indole derivatives 8,15 related to anthramycin skeleton was prepared in good yield from indole-2-carboxylic acid and β-aminoesters 4 through intramolecular cyclisation.

Full text of DOI:10.1016/S0040-4039(03)01703-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6553–6556
First synthesis of pyrrolo[1,2:1%,2%]azepino[5,6-b]indole derivatives
Julien Perron,a Benoˆıt Josephb and Jean-Yves Me´roura,*
aInstitut de Chimie Organique et Analytique, UMR-CNRS 6005, Universite´ d’Orle´ans, BP 6759, 45067 Orle´ans Cedex 02,
France
bLaboratoire de Chimie Organique 1, UMR-CNRS 5622, Universite´ Claude Bernard – Lyon 1, CPE-Baˆtiment 308,
43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
Received 16 April 2003; revised 8 July 2003; accepted 9 July 2003
Abstract—A new family of pyrrolo[1,2:1%,2%]azepino[5,6-b]indole derivatives 8,15 related to anthramycin skeleton was prepared in
good yield from indole-2-carboxylic acid and b-aminoesters 4 through intramolecular cyclisation.
© 2003 Elsevier Ltd. All rights reserved.
The pyrrolo[2,1-c][1,4]benzodiazepine (PDB) antitumor
antibiotics are a well-known class of sequence-selective
DNA-binding agents.1 Among the PDB family,
anthramycin (Fig. 1) have shown significant in vitro
cytotoxicity but have not progressed in clinical trials
due to side effects (cardiotoxicity,…). Improvements to
enhance antitumor potency and to surmount this draw-
back have been done.2 Nevertheless the need for
analogous structures was still of interest.3,4 Recently
Erba et al. have reported the preparation of the
pyrrolo[1,2-c]1,4-diazepine ring A from 2-amidinylin-
dole-3-carbaldehyde.5 This prompts us to report our
own preliminary results.
In continuation of our work in the synthesis of
azepino[3,4-b]indole-1,5-dione framework B6 as
a
potential scaffold for PKC inhibitors, we became inter-
ested in the design of tetracyclic compounds C.
In our synthetic approach of derivatives C, b-
aminoesters 4 with a pyrrolidino structure was first
prepared in a different way described by Benn et al.7
The latter were obtained in three steps from 2-pyrrolidi-
nones 1 (Scheme 1). Compound 1a is commercially
available. Pyrrolidinone 1b was prepared in 99% yield
by selective silylation of commercially available (R)-4-
hydroxy-2-pyrrolidinone (or (S)-4-hydroxy-2-pyrrolidi-
none).8 Boc protection8 on 2-pyrrolidinones 1 was
Figure 1.
Scheme 1. Reagents and conditions: (a) Boc2O (1 equiv.),
DMAP (10% mol), MeCN, rt, 18 h; (a) i. LiBEt3H (1 equiv.),
THF, −78°C, 30 min; ii. (EtO)2P(O)CH2CO2Et (1 equiv.),
NaH (1 equiv.), THF, 2 h; (c) i. TFA/CH2Cl2 1/1, 0°C, 2 h;
ii. Et3N, CH2Cl2, rt, 2 h.
Keywords: anthramycin; indole; pyrrolidine; intramolecular cyclisa-
tion.
* Corresponding author. Tel.: +33 (0)2 38 41 72 81, fax: +33 (0)2 38
49 45 92; e-mail: jean-yves.merour@univ-orleans.fr
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01703-9

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J. Perron et al. / Tetrahedron Letters 44 (2003) 6553–6556
performed to give 2 in 92–97% yield. Reduction of the
lactam function was carried out with super Hydride® in
THF at −78°C,9 the resulting aminal was then treated
with the sodium salt of ethyl phosphonoacetate (1
equiv.) at room temperature. The two-step procedure
afforded 3 from 2 in 83–87% overall yield. Deprotec-
tion of 3 in acidic medium afforded the trifluoroacetate
salt which upon basic treatment gave the cyclic ethyl
aminoesters 4. Compounds 4 were directly used in next
step without purification.
Crude compound 4a was coupled with indole-2-car-
boxylic acid to provide, under classical conditions,
amide 5 in 78% yield. Methylation of the nitrogen
indolic atom was achieved with iodomethane in reflux-
ing acetonitrile to afford 6 in 96% yield. Acid 7 was
obtained by basic hydrolysis (lithium hydroxide) of the
ester 6 in 89% yield. Final cyclisation of 7 in the
presence of PPA was performed at 110°C for 30 min to
give the desired framework 8 in 89% yield (Scheme 2).
The synthesis of the analogous compound 15 with a
ketonic group on the pyrrolidino moiety was more
problematic. Treatment of 1-methyl-indole-2-carboxylic
acid with 4b afforded amide 9 in 71% yield as a mixture
of diastereomers (7/3) which were separated by column
Scheme 4. Reagents and conditions: (a) Bu4N+F− (1 equiv.),
,
THF, rt, 5 min; (b) PDC (3 equiv.), molecular sieves 4 A,
CH2Cl2, rt, 24 h; (c) ethyleneglycol (5 equiv.), PTSA (2
equiv.), toluene reflux, 8 h; (d) 20% aq. HCl, MeOH reflux, 30
min; (e) NaH (2 equiv.), (C2H5O)2P(O)CH2COOC2H5 (2
equiv.), THF, rt, 5 min.
chromatography. Hydrolysis of
9
(mixture of
diastereomers or each one separately) with LiOH
afforded the acid 10 in excellent yield. A first attempt of
cyclisation on one diastereomer (presumably the cis
one) with PPSE in nitromethane provided exclusively
the lactone 11 in 65% yield. The other diastereomer
gave in the same conditions a mixture of compounds
from which lactone 11 is isolated in 30% yield (Scheme
3).
This result indicated the need for a more resistant
hydroxyl protective group. Fluoride deprotection in
THF of the silyl ether 9 afforded after 5 min the
alcohol 12 with a 95% yield. Unfortunately the benzyl
protection of 12 was not possible and gave only a
mixture of degradation products. So the alcoholic func-
tion was further oxidised into the ketonic derivative 13
(88% yield) using PDC. Saponification of 13 immedi-
ately afforded again a degradation. Compared to 7, the
low stability of acid was due to the presence of the keto
group, so an acetal protection was performed on 13 in
the presence of ethyleneglycol and a catalytic amount
of PTSA. We observed to our delight the concomitant
formation of the acetal derivative and traces of cyclised
compound 14. The cyclisation conditions were opti-
mised and finally the treatment of 13 with 5 equiv. of
ethyleneglycol and 2 equiv. of PTSA in refluxing tolu-
ene for 8 h in a Dean Stark afforded the cyclised
derivative 14 in 71% yield (Scheme 4). A TLC monitor-
ing indicates first the formation of acetal derivative
then cyclisation. This data was confirmed by the inert-
ness of the keto ester in absence of ethylene glycol.
Scheme 2. Reagents and conditions: (a) 3a (1 equiv.), EDCI
(1.5 equiv.), DMAP (0.2 equiv.), CH2Cl2, rt, 18 h; (b) K2CO3
(5 equiv.), MeI (5 equiv.), MeCN reflux; (c) LiOH (1.5
equiv.), EtOH, 15 h, rt; (d) PPA, 110°C, 30 min.
Scheme 3. Reagents and conditions: (a) LiOH (1.5 equiv.),
EtOH, rt, 15 h; (b) PPSE, 110°C, 30 min.

J. Perron et al. / Tetrahedron Letters 44 (2003) 6553–6556
6555
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8141–8147.
3. Gregson, S. J.; Howard, P. W.; Corcoran, K. E.; Bar-
cella, S.; Yasin, M. M.; Hurst, A. A.; Jenkins, T. C.;
Kelland, L. R.; Thurston, D. E. Bioorg. Med. Chem. Lett.
2000, 10, 1845–1847 and 1849–1851.
4. Kamal, A.; Suresh Kumar Reddy, G.; Laxma Reddy, K.;
Raghavan, S. Tetrahedron Lett. 2002, 43, 2103–2106.
5. Clerici, F.; Erba, E.; Pocar, D. Tetrahedron 2003, 59,
1667–1671.
6. Chacun-Lefe`vre, L.; Joseph, B.; Me´rour, J.-Y. Tetra-
hedron 2000, 56, 4491–4499.
7. Ru¨eger, H.; Benn, M. Heterocycles 1982, 19, 23–25.
8. Imamura, H.; Shimizu, A.; Sato, H.; Sugimoto, Y.;
Sakuraba, S.; Nakajima, S.; Abe, S.; Miura, K.;
Nishimura, I.; Yamada, K.; Morishima, H. Tetrahedron
2000, 56, 7705–7713.
Scheme 5. Reagents and conditions: (a) NaBH4 (1 equiv.),
MeOH, rt, 5 min; (b) MsCl (5 equiv.), pyridine, rt, 30 min; (c)
DBU (3 equiv.), DMF, reflux, 8 h.
9. Mulzer, J.; Schu¨lzchen, F.; Bats, J.-W. Tetrahedron 2000,
56, 4289–4298.
10. Gillard, A. C.; Alkhader, M.; Rault, S. Heterocycl. Com-
mun. 1996, 2, 409–414.
Deprotection of the ketone occurred by refluxing 14 in
methanol with 20% aq. HCl for 30 min and furnished
15 in 96% yield. The keto group of the pyrrolidino
moiety was expected to be more reactive towards nucle-
ophilic reagents and this was illustrated by treatment of
15 with the ethyl phosphonate anion (2 equiv.) in THF
at room temperature. After 5 min, compound 16 was
obtained as the major product and the sole product
after basic isomerisation, in the mixture, of the exo-
cyclic double bond into the pyrrolidino moiety of the
minor isomer.
11. Physical data of 8: white solid; mp 156–158°C (ethyl
acetate); IR (KBr) w 1640 (CO), 1622 (CO) cm−1 1H
;
NMR (250 MHz, CDCl3) l 1.81–2.10 (m, 3H, CH2),
2.30–2.37 (m, 1H, CH2), 2.76–3.03 (m, 2H, CH2), 3.73–
3.93 (m, 2H, CH2), 4.08 (s, 3H, CH3), 4.24–4.33 (m, 1H,
CH), 7.30–7.41 (m, 3H, Har), 8.49 (d, 1H, J=8.0 Hz,
Har); 13C NMR (62.90 MHz, CDCl3) l 23.2 (CH2), 32.9
(CH3), 33.2 (CH2), 47.2 (CH2), 50.4 (CH2), 54.0 (CH),
110.2 (CH), 116.0 (C), 123.7 (CH), 123.8 (CH), 125.3 (C),
125.5 (CH), 135.3 (C), 138.2 (C), 159.5 (CO), 194.3 (CO);
LRMS (CI) m/z 269 (MH+); HRMS (CI) m/z calcd for
C16H17N2O2 (MH+): 269.1290. Found: 269.1287. Com-
pound 15: white solid; mp 216–218°C (ethyl acetate); IR
The keto group of compound 15 was also reduced into
the alcohol 17 (80% yield) by NaBH4 in MeOH. Com-
pound 17 was treated with methanesulfonyl chloride as
described by Rault et al.10 to lead to the mesylate 18
(79% yield) which was heated in the presence of DBU
to give both compounds 19 and 2011 which were
purified by column chromatography (73% overall yield
3/1 ratio) (Scheme 5).
(KBr) w 1735 (CO), 1641 (CO), 1607 (CO) cm−1 1H
;
NMR (250 MHz, CDCl3) l 2.54 (dd, 1H, J=3.2, 19.2
Hz, CH2), 2.87 (dd, 1H, J=1.2, 19.2 Hz, CH2), 3.08–3.23
(m, 2H, CH2), 4.08 (s, 3H, CH3), 4.16 (d, 1H, J=20.1 Hz,
CH2), 4.34 (d, 1H, J=20.1 Hz, CH2), 4.81–4.91 (m, 1H,
CH), 7.33–7.45 (m, 3H, HAr), 8.48 (d, 1H, J=8.4 Hz,
1HAr); 13C NMR (62.90 MHz, CDCl3) l 32.9 (CH3), 43.5
(CH2), 51.1 (CH2), 51.5 (CH), 53.0 (CH2) 110.4 (CH),
116.6 (C), 123.9 (CH), 124.1 (CH), 125.2 (C), 126.1 (CH),
133.4 (C), 138.6 (C), 160.4 (CO), 193.0 (CO), 207.0 (CO);
LRMS (CI) m/z 283 (MH+); HRMS (CI) m/z calcd for
C16H15N2O3 (MH+): 283.1082. Found: 283.1081. Com-
pound 16: white solid; mp 138–140°C (ethyl acetate); IR
In summary, a new pyrrolo[1,2:1%,2%]azepino[5,6-b]-
indole family was developed in fair yield. We are now
investigating the reactivity of the system and more
particularly the position 4 of the azepino ring which is
involved in biological properties.
Acknowledgements
(KBr) w 1735 (CO), 1637 (CO), 1612 (CO) cm−1 1H
;
NMR (250 MHz, CDCl3) l 1.30 (t, 3H, J=7.3 Hz, CH3),
2.53 (dd, 1H, J=3.2, 18.1 Hz, CH2), 2.81 (d, 1H, J=18.1
Hz, CH2), 3.22 (s, 2H, CH2), 3.23–3.34 (m, 2H, CH2),
4.09 (s, 3H, CH3), 4.19 (q, 2H, J=7.3 Hz, CH2), 4.70–
4.80 (m, 1H, CH), 7.03 (s, 1H, CHꢀ), 7.34–7.44 (m, 3H,
HAr), 8.57 (d, 1H, J=8.4 Hz, HAr); 13C NMR (62.90
MHz, CDCl3) l 14.4 (CH3), 32.9 (CH3), 34.2 (CH2), 40.2
(CH2), 51.1 (CH2), 54.4 (CH), 61.3 (CH2), 110.3 (CH),
116.1 (C), 118.9 (C), 124.0 (CH), 124.0 (CH), 125.3 (CH),
125.5 (C), 125.9 (CH), 134.2 (C), 138.7 (C), 156.2 (CO),
170.2 (CO), 193.3 (CO); LRMS (CI) m/z 353 (MH+);
HRMS (CI) m/z calcd for C20H21N2O4 (MH+): 353.1501.
Found: 353.1504. Compound 19: white solid; mp 160–
This research work was supported by a grant from the
‘MESNR’ to J.P.
References
1. Thurston, D. E.; Bose, D. S.; Howard, P. W.; Jenkins, T.
C.; Leoni, A.; Baraldi, P. G.; Guiotto, A.; Cacciari, B.;
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P. W.; Leoni, A.; Croker, S. J.; Jenkins, T. C.; Neidle, S.;

6556
J. Perron et al. / Tetrahedron Letters 44 (2003) 6553–6556
162°C (ethyl acetate); IR (KBr) w 1644 (CO), 1615 (CO)
solid; mp 140–142°C (ethyl acetate); IR (KBr) w 1643
(CO), 1615 (CO) cm−1 1H NMR (250 MHz, CDCl3) l
1
cm−1; H NMR (250 MHz, CDCl3) l 2.48–2.58 (m, 1H,
;
2.90–2.95 (m, 2H, CH2), 4.12 (s, 3H, CH3), 4.55–4.59 (m,
2H, CH2), 5.00–5.08 (m, 1H, CH), 5.76–5.80 (m, 1H,
CHꢀ), 5.99–6.04 (m, 1H, CHꢀ), 7.33–7.45 (m, 3H, HAr),
8.50 (d, 1H, J=8.3 Hz, HAr); 13C NMR (62.90 MHz,
CDCl3) l 33.0 (CH3), 49.5 (CH2), 53.8 (CH2), 60.8 (CH),
110.3 (CH), 116.2 (C), 123.9 (CH), 124.0 (CH), 125.5 (C),
125.7 (CH), 125.8 (CH), 128.8 (CH), 134.8 (C), 138.4 (C),
159.4 (CO), 193.3 (CO); MS m/z 267 (MH+); LRMS (CI)
m/z 267 (MH+); HRMS (CI) m/z calcd for C16H14N2O2
(MH+): 267.1133. Found: 267.1136.
CH2), 2.80 (d, 1H, J=18.0 Hz, CH2), 3.17–3.32 (m, 2H,
CH2), 4.11 (s, 3H, CH3), 4.67–4.78 (m, 1H, CH), 5.42–
5.46 (m, 1H, CHꢀ), 7.08–7.12 (m, 1H, CHꢀ), 7.33–7.42
(m, 3H, HAr), 8.50 (d, 1H, J=8.5 Hz, HAr); 13C NMR
(62.90 MHz, CDCl3) l 32.9 (CH3), 37.8 (CH2), 51.1
(CH2), 53.8 (CH), 110.3 (CH), 111.7 (CH), 116.2 (C),
124.0 (2CH), 125.5 (C), 125.9 (CH), 127.7 (CH), 134.4
(C), 138.7 (C), 156.4 (CO), 193.3 (CO); LRMS (CI) m/z
267 (MH+); HRMS (CI) m/z calcd for C16H15N2O2
(MH+): 267.1133. Found: 267.1135. Compound 20: white