Selective reduction of aromatic azides with hexamethyldisilathiane: Synthesis of new 2-azidopyrrolo[2,1-c][1,4]benzodiazepines

Article abstract of DOI:10.1016/j.tetlet.2004.02.148

2-Azidopyrrolobenzodiazepines have been synthesized via cyclization of ω-azidocarbonyl compounds employing hexamethyldisilathiane by selectively reducing the aryl azido functionality.

Full text of DOI:10.1016/j.tetlet.2004.02.148

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 3499–3501
Selective reduction of aromatic azides with hexamethyldisilathiane:
synthesis of new 2-azidopyrrolo[2,1-c][1,4]benzodiazepines
Ahmed Kamal,* K. Laxma Reddy, G. Suresh Kumar Reddy and B. S. Narayan Reddy
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 6 January 2004;revised 10 February 2004;accepted 27 February 2004
Abstract—2-Azidopyrrolobenzodiazepines have been synthesized via cyclization of x-azidocarbonyl compounds employing hexa-
methyldisilathiane by selectively reducing the aryl azido functionality.
Ó 2004 Elsevier Ltd. All rights reserved.
Pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) a group of
potent naturally occurring antitumour antibiotics from
various Streptomyces species are of considerable interest
due to their potential as antitumour agents, gene regu-
lators and DNA probes.1 Well known members of this
group include abbeymycin (1a), chicamycin A and B
(1b), anthramycin, tomaymycin (2), neothramycin A
and B, sibiromycin and DC-81.2 The cytotoxicity and
antitumour activity of these agents are attributed to
their property of sequence selective covalent binding to
the N2 of guanine in the minor groove of duplex DNA
via an acid-labile aminal bond to the electrophilic imine
at the N10–C11 position. The (S)-configuration at the
chiral C11a-position provides the PBD structure with
the necessary right handed twist to fit snugly within the
minor groove of DNA spanning three base pairs with a
preference for the Pu–G–Pu sequence.3 The PBDs are
being used in the development of gene targeting agents
with the potential to down-regulate genes of therapeutic
interest. The major problems encountered in the syn-
thesis of PBDs are the installation of the sensitive
N10-C11 imine or carbinolamine functionality and
racemization at the C11a position. In recent years, a
number of hybrid molecules containing the PBD ring
system have been synthesized to improve the DNA
binding ability and sequence selectivity.4;5 We have been
interested in the structural modifications of the PBD
ring system and the development of new synthetic
strategies.6 In continuation of these efforts, we would
like to report an efficient synthesis of a novel 2-azi-
dopyrrolobenzodiazepine to probe its DNA sequence
selective binding ability and cytotoxicity.
10
H
OCH3
H
9
6
11
N
R
N
8
HO
H
1
2
N 11a
3
7
5
R'
N
H3CO
OH
O
O
R = R' = H; Abbeymycin (1a)
Tomaymycin (2)
R = OH, R' = OCH3 ; Chicamycin B (1b)
N
H
N
H
N
N
F
N3
O
O
3
4
H
N
O
H
N
N3
O
5
Keywords: Pyrrolobenzodiazepines;Reductive cyclization;Antitumour
agents.
It is well known in the literature that C-ring hydroxy
substitution plays an important role in the biological
activity of PBDs, examples being naturally occurring
PBDs such as chicamycin A and B (1b),7a neothramycin
A and B7b and abbeymycin (1a).7c According to SAR
* Corresponding author. Tel.: +91-40-27193157;fax: +91-40-271931-
89;e-mail addresses: ahmedkamal@iict.ap.nic.in, ahmedkamal@iict.
res.in
Present address: Department of Medicinal Chemistry, University of
Kansas, Lawrence, KS 66045, USA.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.148

3500
A. Kamal et al. / Tetrahedron Letters 45 (2004) 3499–3501
Table 1. Yields and molecular ions observed for PBD analogues 4a–c
and 5a–c
studies, C2 exo and endo unsaturation enhances the
DNA binding affinity and cytotoxicity of this class of
compounds, for example, tomaymycin.8 Thurston and
co-workers have reported the synthesis of C2/C20-
unsaturated DC-81 analogues and their dimers (SJG-
136), which demonstrates the importance of C2/C20-exo-
unsaturation in enhancing DNA-binding affinity and
cytotoxicity.9 Recently, the effect of fluorination at the
C2-position of the PBD ring system (e.g., 3) on the
biological activity particularly DNA binding potential
has been investigated.10 In view of the importance of
C-ring substitution,11 we have developed an efficient
synthetic pathway for the introduction of an azido
group at the C2-position in the PBD molecule. In the
literature, there are some reports on the synthesis of
pyrrolobenzodiazepines employing an intramolecu-
lar aza-Wittig approach using triphenylphosphine or
tributylphosphine.12 In our synthetic route we have
Entry
R
Yields (%)a
EIMS
4a
4b
4c
5a
5b
5c
H
69
65
62
74
68
65
241
301
377
257
317
393
7-OMe, 8-OMe
7-OMe, 8-OBn
H
7-OMe, 8-OMe
7-OMe, 8-OBn
a Overall yields.
give the corresponding azidoesters 6. The hydroxy
group of the proline moiety was activated as its mesyl
ether 7 by treatment with MsCl and triethylamine and
the mesylates treated with NaN3 in DMF to afford the
bis-azides 8, which were reduced with HMDST in
MeOH to give the 2-azido PBD-5,11-diones 5 quanti-
tatively. The ester functionality of the bis-azides 8 was
also reduced with DIBAL-H at À78 °C to give the cor-
responding azidoaldehydes without detectable racemi-
zation, which were reacted further with HMDST in
MeOH at room temperature, to afford the 2-azido PBD
imines 4 in good yields16 (Table 1).
employed
a
mild and selective reducing agent,
(CH3)3SiSSi(CH3)3 [hexamethyldisilathiane (HMDST)]
which is in continuation of our earlier studies on the
reductive cyclization of azides.13 Our previous attempts
to reduce the azido functionality by triphenylphosphine
produced products that could not be isolated, probably
because of the reduction of both the aryl and alkyl azido
functionalities, whereas, C-2 azido substituted PBD
amidines14 and dilactams15 have been prepared by azi-
dation of mesyl or tosyl ethers of the cyclic PBD ami-
dine or dilactams. There are no reports on the synthesis
of imine containing 2-azido PBDs.
In summary, a mild, efficient and selective reduction of
an aromatic azido functionality in the presence of alkyl
azides employing HMDST has been developed and used
to prepare 2-azido PBDs in good yields. The anticancer
activity and DNA binding affinity studies of these
compounds will be published in due course.
Compounds 4 and 5 were synthesized according to the
routes outlined in Scheme 1. 2-Azidobenzoic acids were
coupled with trans-4-hydroxy-
L
-proline methyl ester to
Acknowledgements
N3
N3
i
COOCH3
R
K.L.R. and G.S.K.R. are grateful to CSIR (New Delhi)
for the award of Senior Research Fellowships.
R
COOCH3
COOH
N
OH
O
HCl.HN
6a-c
OH
ii
References and notes
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N3
COOCH3
N3
COOCH3
OMs
R
R
iii
N
N
N3
O
O
8a-c
7a-c
iv, v
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H
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N
N
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N3
N3
O
O
4a-c
5a-c
Scheme 1. Reagents and conditions: (i) SOCl2, triethylamine, DMF,
C6H6 (ii) MsCl, triethylamine, CH2Cl2 (iii) NaN3, DMF, 50 °C, (iv)
DIBAL-H, CH2Cl2, À 78 °C (v) HMDST, MeOH, rt, 4 h.

A. Kamal et al. / Tetrahedron Letters 45 (2004) 3499–3501
3501
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32
D
diazepine-5,11-dione 5a: ½aŠ þ596 (c 1, MeOH); 1H NMR
(200 MHz, DMSO-d6): d 2.25–2.40 (m, 1H), 3.00–3.10 (m,
1H), 3.60–3.70 (m, 1H), 3.80–3.95 (dd, J ¼ 6:2 Hz,
J ¼ 13:7 Hz, 1H), 4.05–4.15 (m, 1H), 4.25–4.35 (m, 1H),
7.10–7.20 (m, 2H), 7.40–7.45 (m, 1H), 7.90 (d, J ¼ 10:3 Hz,
1H), 10.20 (s, 1H);EIMS: m=z 257 [M]þÅ;HRMS: 257.0912
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m
max/cmÀ1 2933,
2107, 1689, 1617, 1451, 1383, 1213, 1046, 750;mp: 217–
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220 °C.
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1.75 mmol) in methanol (10 mL) was treated with 2–3 equiv
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32
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4a: ½aŠ À138 (c 0.5, MeOH); 1H NMR (200 MHz, DMSO-
d6): d D2.20–2.30 (m, 1H), 3.20–3.30 (m, 1H), 3.50–3.60 (m,
1H), 3.90–4.00 (m, 2H), 4.25– 4.30 (m, 1H), 6.75–6.80 (m,
1H), 6.90–7.00 (m, 1H), 7.15–7. 25 (m, 2H), 7.60 (d,
J ¼ 6 Hz, 1H);EIMS: m=z 241 [M]þÅ;HRMS: 241.0963
(calculated), 241.0966 (observed);IR:
m
max/cmÀ1 3311,
2103, 1618, 1448, 1211, 1145, 638;mp: 101–104 °C.