Reductive cyclization of ω-azido/nitrocarbonyl compounds by samarium iodide: A facile preparation of DNA-binding pyrrolo[2,1-c][1,4]benzodiazepine and its dimers

Article abstract of DOI:10.1016/S0040-4039(00)01524-0

An efficient synthesis of pyrrolo[2,1-c][1,4]benzodiazepines via reductive cyclization of ω-azido/nitrocarbonyl compounds employing samarium iodide is described. This methodology has also been extended for the preparation of DNA-crosslinking DC-81 dimers. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01524-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8631–8634
Reductive cyclization of v-azido/nitrocarbonyl compounds
by samarium iodide: a facile preparation of DNA-binding
pyrrolo[2,1-c][1,4]benzodiazepine and its dimers†
Ahmed Kamal,* E. Laxman and P. S. M. M. Reddy
Division of Organic Chemistry-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 16 June 2000; revised 20 August 2000; accepted 7 September 2000
Abstract
An efficient synthesis of pyrrolo[2,1-c][1,4]benzodiazepines via reductive cyclization of v-azido/nitrocar-
bonyl compounds employing samarium iodide is described. This methodology has also been extended for
the preparation of DNA-crosslinking DC-81 dimers. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: reductive cyclization; pyrrolobenzodiazepines; DNA-binding; samarium iodide; DC-81 dimers.
DNA-binding molecules are presently attracting interest due to their involvement in carcino-
genesis and their use as antitumor agents and probes of DNA structure.1 The pyrrolo[2,1-
c][1,4]benzodiazepine (PBD) family of DNA-binding antitumor antibiotics (anthramycin) has
been extensively studied as a potential source of antitumor agents and DNA probes.2,3 The
naturally occurring PBDs have been isolated from various Streptomyces species. It has been well
established that they exert their biological activity through covalent binding to the exocyclic N2
of guanine in the minor groove of DNA.4
* Corresponding author.
†
IICT communication no. 4568.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01524-0

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Many molecules based on the PBD ring system have been synthesized to improve upon their
biological profile. In this search C-7 or C-8 linked dimers of PBD have been synthesized which
are capable of sequence selective DNA-interstrand cross-linking.5,6 For example, DC-81 dimers
of this type are highly cytotoxic and very efficient sequence selective cross-linking agents.7,8
Recently, new DNA-interstrand cross-linking, C-2 linked PBD dimers have also been synthe-
sized.9 Furthermore, hybrid molecules containing the PBD ring system have been recently
reported with interesting minor groove DNA-binding properties.10,11
In view of the importance of these molecules we have been interested in the structural
modifications of naturally occurring PBDs to improve their DNA-binding potential and
sequence selectivity. We have also been involved in the development of new synthetic strategies
for the PBD ring system.12–15 In this endeavor, we wish to report a new approach of practical
significance based on a reductive cyclization strategy for the PBD ring system and its dimers
employing SmI2.
The precursors, N-(2-azido/nitro-benzoyl)pyrrolidine-2-carboxaldehydes (1) were prepared by
literature methods.16 These upon reductive cyclization with SmI2, afforded the desired PBD
imines (2) in 70–72% yields.17 It has been observed that reduction of either the azido or the nitro
group does not have much effect on the yields of the desired product (2), except for the reductive
cyclization of azido compounds that takes place in 1.5 h when compared to nitro compounds
which is completed in 2 h (Scheme 1).
Scheme 1. (i) SmI2, THF, rt, 1.5–2 h. (a) R=R1=H; (b) R=H, R1=CH3; (c) R=OH, R1=OCH3
This approach has also been extended to the synthesis of DC-81 dimers. The precursor,
methyl-(2S)-(4-hydroxy-5-methoxy-2-nitrobenzoyl)pyrrolidine-2-carboxylate (3), was synthe-
sized as described in the literature.18 This was alkylated using the dibromoalkanes (4) to obtain
the 4,4%-(alkane-a,v-diyldioxy)bis[methyl-(2S)-N-(5-methoxy-2-nitrobenzoyl)pyrrolidine-2-car-
boxylates] (5).19 There upon reduction with DIBAL-H gave the nitroaldehydes (6), which on
reductive cyclization with SmI2 afforded DSB-120 (7, n=3) and other DC-81 dimers in 18–20%
overall yields20 (Scheme 2).
The significant feature of this method is that it addresses many of the difficulties encountered
by the literature procedures, particularly solubility aspects after the dimerization process.6,8 In
the present method, the precursor 3 is synthesized in a facile manner and dimerized later, which
leads to an improvement in the yield and ease of work up. Furthermore, this process avoids
contamination by mercuric salts unlike the well-known ethanedithiol deprotective cyclization
approach employing HgCl2.
In summary, we have developed a new azido as well as nitro reductive cyclization route
employing SmI2 for the preparation of the PBD ring system, and extended this work to include
dimers resulting not only in improved yields but also a facile synthetic sequence. This work will
assist investigators in the preparation of similar biologically significant DNA-interactive dimers.

8633
Scheme 2. (i) K2CO3, acetone, reflux, 36–48 h, 80–90%; (ii) DIBAL-H (4 equiv.), CH2Cl2, −78°C, 45 min, 72–78%;
(iii) SmI2, THF, 2 h, 55–63%
Acknowledgements
One of the authors (E.L.) is thankful to the CSIR, New Delhi, for the award of a Senior
Research Fellowship.
References
1. Neidle, S.; Thurston, D. E. In New Target for Cancer Chemotherapy; Kerr, D.; Workman, P., Eds. DNA
sequences as targets for new anticancer drugs. CRC: Boca Raton, FL, 1994; pp. 159–175.
2. Thurston, D. E.; Puvvada, M. S.; Neidle, S. Eur. J. Cancer 1994, 30A, 567.
3. Thurston, D. E. In Molecular Aspects of Anticancer Drug–DNA Interactions; Neidle, S.; Waring, M. J., Eds.
Advances in the study of pyrrolo[2,1-c][1,4]benzodiazepine antitumor antibiotics. Macmillan: Basingstoke, UK,
1993; Vol. 1, pp. 54–87.
4. Remers, W. A. The Chemistry of Antitumour Antibiotics; Wiley Interscience: New York, 1988; Vol. 2, pp. 28–92.
5. Farmer, J. D.; Rudnicki Jr., S. M.; Suggs, J. W. Tetrahedron Lett. 1988, 29, 5105.
6. Bose, D. S.; Thompson, A. S.; Ching, J. A.; Hartley, J. A.; Berardini, M. D.; Jenkins, T. C.; Neidle, S.; Hurley,
L. H.; Thurston, D. E. J. Am. Chem. Soc. 1992, 114, 4939.
7. Jenkins, T. C.; Hurley, L. H.; Neidle, S.; Thurston, D. E. J. Med. Chem. 1994, 37, 4529.

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8. Thurston, D. E.; Bose, D. S.; Thompson, A. S.; Howard, P. W.; Leoni, A.; Croker, S. J.; Jenkins, T. C.; Neidle,
S.; Hartley, J. A.; Hurley, L. H. J. Org. Chem. 1996, 61, 8141.
9. Reddy, B. S. P.; Damayanthi, Y.; Lown, J. W. Synlett 1999, 7, 1112.
10. Baraldi, P. G.; Balboni, G.; Cacciari, B.; Guiotto, A.; Manfredini, S.; Romagnoli, R.; Spalluto, G.; Thurston, D.
E.; Howard, P. W.; Bianchi, N.; Rutigliano, C.; Mischiati, C.; Gambari, R. J. Med. Chem. 1999, 42, 5131.
11. Damayanthi, Y.; Reddy, B. S. P.; Lown, J. W. J. Org. Chem. 1999, 64, 290.
12. Kamal, A.; Rao, N. V. Tetrahedron Lett. 1995, 36, 4299.
13. Kamal, A.; Damayanthi, Y.; Reddy, B. S. N.; Lakshminarayana, B.; Reddy, B. S. P. Chem. Commun. 1997, 1015.
14. Kamal, A.; Rao, M. V.; Reddy, B. S. N. Khim. Getrotsikl. Soedin. Chem. (Chem. Heterocycl. Compd.) 1998, 12,
1588.
15. Kamal, A.; Reddy, B. S. N.; Reddy, G. S. K. Synlett 1999, 8, 1251.
16. Kamal, A.; Reddy, B. S. N.; Reddy, B. S. P. Bioorg. Med. Chem. Lett. 1997, 7, 1825.
17. Preparation of compound 2: To a stirred 0.1 M solution of SmI2 in THF (12.5 ml, 2.5 equiv.) was added
dropwise a solution of 1 (122 mg, 0.5 mmol) in THF (5 ml) under a nitrogen atmosphere, at room temperature
and the stirring was continued for 1.5 h. After completion of the reaction, as indicated by TLC (ethyl acetate),
the solvent was evaporated, the mixture was dissolved in CHCl3 and then it was washed with saturated K2CO3.
The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by
flash column chromatography using ethyl acetate–hexane (9:1) to obtain the pure imine (2) in good yields.
1
Spectral data of compound 2a: H NMR: (CDCl3) l 1.90–2.36 (m, 4H), 3.52–3.92 (m, 3H), 7.28–7.56 (m, 3H),
7.78 (d, 1H, J=4.6 Hz), 8.05 (d, 1H, J=5.2 Hz); MS: m/z 200 (M+, 100) 171, 160, 144, 120, 103, 83, 70.
18. Kamal, A.; Reddy, B. S. P.; Reddy, B. S. N. Tetrahedron Lett. 1996, 37, 2281.
19. Preparation of compound 5: To a stirred solution of 1,3-dibromopropane (202 mg, 1.0 mmol) in dry acetone (50
ml) was added anhydrous potassium carbonate (1.38 g, 10.0 mmol) and the monomer nitroester 3 (648 mg, 2.0
mmol). The reaction mixture was then heated under reflux for 48 h. After completion of the reaction, as indicated
by TLC, using ethyl acetate–hexane as a solvent system, the potassium carbonate, was removed by filtration and
the acetone evaporated under vacuum. The reaction mixture was purified by column chromatography using ethyl
1
acetate–hexane (8:2) as eluent to afford pure dimer 5 in quantitative yields. Spectral data of compound 5: H
NMR (CDCl3): 1.90–2.12 (m, 2H), 2.22–2.46 (m, 8H), 3.50–3.65 (m, 4H), 3.70 (s, 6H), 3.82 (s, 6H), 4.18–4.34 (t,
4H), 4.50–4.82 (m, 2H), 6.80 (s, 2H), 7.32 (s, 2H); MS: m/z 689 (MH+).
20. Preparation of DC-81 dimer (7): The dimeric nitroaldehyde (6a, 125 mg, 0.2 mmol) in THF (5 ml) was added
slowly to a stirred 0.1 M solution of SmI2 in THF (10 ml, 5 equiv.) at room temperature under a nitrogen
atmosphere. The reaction was continued for 2 h and after completion of the reaction, the THF was evaporated
under reduced pressure. This was dissolved in chloroform and washed with saturated K2CO3. The organic layer
was dried over MgSO4 and evaporated under reduced pressure, then purified by flash chromatography using
CHCl3:MeOH (9.5:0.5) as eluent to give the pure DC-81 dimer 7a in 60% yield. Spectral data of compound 7a:
1H NMR (CDCl3): l 2.01–2.17 (m, 2H), 2.27–2.44 (m, 8H), 3.50–3.86 (m, 6H), 3.92 (s, 6H), 4.24–4.34 (m, 4H),
6.86 (s, 2H), 7.51 (s, 2H), 7.65 (d, 2H, J=4.4 Hz); FAB MS: m/z 533 (MH+).
.