Synthesis of pyrrolo[2,1-c][1,4]benzodiazepines via reductive cyclization of ω-Azido carbonyl compounds by TMSI: An efficient preparation of antibiotic DC-81 and its dimers

Article abstract of DOI:10.1016/S0960-894X(00)00468-6

ω-Azido carbonyl compounds on reaction with trimethylsilyl iodide (in situ prepared from TMSCI/NaI) led to the formation of diazepine imines in good yields under mild conditions. This methodology has been applied to the parent unsubstituted pyrrolobenzodiazepine, the natural product DC-81 and its dimers. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0960-894X(00)00468-6

Bioorganic & Medicinal Chemistry Letters 10 (2000) 2311±2313
Synthesis of Pyrrolo[2,1-c][1,4]benzodiazepines via Reductive
Cyclization of !-Azido Carbonyl Compounds by TMSI:
An Ecient Preparation of Antibiotic DC-81 and its Dimersy
Ahmed Kamal,* E. Laxman, N. Laxman and N. Venugopal Rao
Division of Organic Chemistry Ð I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 18 May 2000; accepted 4 August 2000
AbstractÐo-Azido carbonyl compounds on reaction with trimethylsilyl iodide (in situ prepared from TMSCl/NaI) led to the for-
mation of diazepine imines in good yields under mild conditions. This methodology has been applied to the parent unsubstituted
pyrrolobenzodiazepine, the natural product DC-81 and its dimers. # 2000 Elsevier Science Ltd. All rights reserved.
In recent years, there has been considerable interest in
ring systems such as pyrrolo[2,1-c][1,4]benzodiazepines
(PBDs) that can recognise and bind to speci®c sequences
of DNA.1 3 These compounds have been obtained
naturally from Streptomyces species and have been syn-
thesized with structural modi®cations for improvement
in sequence speci®c binding. These molecules exert the
biological activity by covalently binding to the N2 of
guanine in the minor groove of DNA through the imine
or imine equivalent functionality at N10±C11 of the
PBD ring system and thus interfere with DNA function.
Most of the molecules interact with DNA in a sequence-
selective manner and as such have potential as anti-
tumour agents and gene targeting drugs.4,5 In the last
few years, various strategies.6 20 have been proposed for
the synthesis of these antibiotics and have met with
varying degrees of success having di€erent limitations.21
It has been found that the introduction of the imine at
N10±C11 position has usually given problems because
of the reactivity of these functional groups.
The treatment of 1 with TMSCl/NaI (in situ preparation
of TMSI) gave pyrrolo[2,1-c][1,4]benzodiazepine-5,11-
diones (3a±d), in 80±85% yields. These dilactams have
been employed as intermediates for the synthesis of
naturally occurring PBD imines.24 26 Whereas, the
reduction of 1 with DIBAL-H gives the corresponding
(2S)-N-(2-azidobenzoyl)pyrrolidine-2-carboxaldehydes (2)
and this upon reaction with TMSCl/NaI at room tem-
perature led to PBD imines (4a±d) in 70±75% yields
(Scheme 1).27
The usefulness of this methodology has not only been
demonstrated for DC-81 (4c), but also for the synthesis
of the dimers of DC-81. Recently, DC-81 dimers linked
through their C-8 position have been investigated as bis
functional alkylating agents capable of cross-linking
DNA.28 These dimers are highly toxic for human cell
lines with a preference for six base pair sequences.29 In
view of the biological importance of these PBD dimers30
and our investigations in the design and synthesis of
structurally modi®ed PBD analogues31 33 it has been
considered of interest to explore a versatile synthetic
strategy for the DC-81 dimers. It is envisaged that the
azido reductive approach is a potential method of prac-
tical signi®cance. In the present methodology DC-81
dimers have been prepared starting from bis[2-methoxy-
4-(methoxy carbonyl)-5-nitrophenoxy] alkanes34 (5a±c).
We have earlier shown the reduction of azide to amines
employing TMSCl/NaI.22 This prompted us to study
the reaction of trimethylsilyl iodide (TMSI) with o-azido
carbonyl compounds for the formation of the diazepine
ring system. Therefore, this procedure has been illustrated
by employing it for the DNA binding PBD antibiotics. The
precursors methyl-(2S)-N-(2-azidobenzoyl)-pyrrolidine-2-
carboxylates (1) have been prepared by literature method.23
The reduction of 5a±c followed by diazotization and
hydrolysis gave the corresponding azido acids (6a±c).
Coupling of azido acids with l-proline followed by
esteri®cation a€orded the bis amides (7a±c). This upon
reaction with TMSCl/NaI gave the corresponding PBD
yIICT Communication No. 4537.
*Corresponding author. Tel.: +91-40-717-3874, ext. 2638; fax: +91-
40-717-0512; e-mail: ahmedkamal@iict.ap.nic.in
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00468-6

2312
A. Kamal et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2311±2313
dimer dilactams (8a±c) in 50±55% yields. Whereas,
reduction of ester functionality with DIBAL-H gives
the corresponding azido carboxaldehydes (9a±c) and
®nally reductive cyclization with TMSCl/NaI at room
temperature a€ords the DC-81 dimers (10a±c) in 40±
45% yields (Scheme 2).35 This is for the ®rst time an
ecient synthesis of C-8 linked pyrrolobenzodiazepine
imines via an azido reductive approach has been devel-
oped.
In conclusion, an ecient azido reductive cyclization
process employing TMSCl/NaI (in situ preparation of
TMSI) towards the synthesis of PBD dilactams and
DNA interactive PBD imines under mild conditions has
been demonstrated. Furthermore, this methodology has
also been extended for the synthesis of DNA interstrand
cross-linking PBD dimers in their imine (DC-81 dimers)
and dilactam forms.
Acknowledgements
The authors (E.L. & N.L.) are thankful to CSIR (New
Delhi) for the award of Senior Research Fellowships.
Scheme 1. Reagents and conditions: (i) DIBAL-H, CH2Cl2, 78 ꢀC,
45 min; (ii) TMSCl/NaI, MeCN, rt, 45 min.
References and Notes
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Scheꢀme 2. Reagents and conditions: (i) SnCl4/HNO3, CH2Cl2,
ꢀ
.
25 C, 5 min; (ii) NaBH4, NiCl2 6H2O, CH2Cl2, 0±5 C, 30 min; (iii)
NaNO2, H2SO4/H2O, 0 ꢀC, NaN3; (iv) 2 N NaOH; (v) SOCl2, C6H6,
3 h, 2(S)-proline, THF, Et3N, H2O, 1 h; (vi) SOCl2, C6H6, MeOH; (vii)
DIBAL-H, 78 ꢀC, CH2Cl2, 45 min; (viii) TMSCl/NaI, MeCN, rt,
45 min.

A. Kamal et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2311±2313
2313
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27. Typical procedure for the synthesis of 4a: To a stirred
solution of 2a (244 mg, 1 mmol) in acetonitrile (10 mL) NaI
(298 mg, 2 mmol) was added under N2 atmosphere at room
temperature. After stirring for 5 min. trimethylsilyl chloride
(217 mg, 2 mmol) in acetonitrile (3 mL) was added at same
temperature and the stirring was continued for 45 min. After
completion of the reaction indicated by TLC, ethyl acetate
(20 mL) was added and the reaction mixture was washed
with 10% sodium thiosulphate. The organic layer was dried
over sodium sulphate, evaporated under reduced pressure and
then puri®ed by column chromatography on silica gel
(chloroform:methanol 9.8:0.2) as eluent to give the pure com-
pound 4a in 75% yield. 1H NMR (CDCl3): d 1.56±2.48 (m, 4H),
3.20±3.89 (m, 3H), 7.10±7.59 (m, 3H), 7.66 (d, 1H, J=4.2 Hz),
8.02 (d, 1H, J=5.8 Hz); IR (CHCl3): 3300, 2975, 2875,
1615, 1570, 1480, 1240, 1165, 860, 830 cm 1; MS: m/e 200
(M+100).
33. Damayanthi, Y.; Reddy, B. S. P.; Lown, J. W. J. Org.
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P. W.; Leoni, A.; Croker, S. J.; Jenkins, T. C.; Neidle, S.;
Hartley, J. A.; Hurley, L. H. J. Org. Chem. 1996, 61, 8141.
35. Typical procedure for the synthesis of 10a: To a stirred
solution of 9a (310 mg, 0.5 mmol) in acetonitrile (10 mL) NaI
(298 mg, 2 mmol) was added under N2 atmosphere at room
temperature. After stirring for 5 min. trimethylsilyl chloride
(217 mg, 2 mmol) in acetonitrile (3 mL) was added at same
temperature and the stirring was continued for 45 min. After
completion of the reaction indicated by TLC, ethyl acetate
(20 mL) was added and the reaction mixture was washed with
10% sodium thiosulphate. The organic layer was dried over
sodium sulphate and evaporated under reduced pressure.
Puri®cation of the crude material by column chromatography
on silica gel using chloroform and methanol (1:9) as eluent
28. Bose, D. S.; Thompson, A. S.; Ching, J.; Hartley, J. A.;
Berardini, M. D.; Jenkins, T. C.; Neidle, S.; Hurley, L. H.;
Thurston, D. E. J. Am. Chem. Soc. 1992, 114, 4939.
29. Mountzouris, J. A.; Wang, J.-J.; Thurston, D. E.; Hurley,
L. H. J. Med. Chem. 1994, 37, 3132.
1
gave the pure compound 10a in 45% yield. H NMR: 1.95±
2.15 (m, 4H); 2.25 (m, 6H); 3.45±3.85 (m, 6H); 3.89 (s, 6H);
4.15±4.28 (t, 4H); 6.78 (s, 2H); 7.42 (s, 2H); 7.60 (d, 2H); MS
(FAB): 533 (M+H+).