A new approach for the solid-phase synthesis of pyrrolo[2,1-c][1,4] benzodiazepines involving reductive cleavage

Article abstract of DOI:10.1016/j.tetlet.2004.08.090

A methodology based on reductive cleavage followed by cyclization, for the solid-phase synthesis of pyrrolo[2,1-c][1,4]benzodiazepines employing DIBAL-H, is described.

Full text of DOI:10.1016/j.tetlet.2004.08.090

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 7667–7669
A new approach for the solid-phase synthesis of
pyrrolo[2,1-c][1,4]benzodiazepines involving reductive cleavage
*
Ahmed Kamal, K. Laxma Reddy, V. Devaiah, N. Shankaraiah and Y. Narasimha Reddy
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 25 June 2004; revised 12 August 2004; accepted 17 August 2004
Abstract—A methodology based on reductive cleavage followed by cyclization, for the solid-phase synthesis of pyrrolo[2,1-
c][1,4]benzodiazepines employing DIBAL-H, is described.
ꢀ
2004 Elsevier Ltd. All rights reserved.
Solid-phase combinatorial chemistry has presently be-
come a very useful methodology for the generation of
libraries of new molecules with biological properties.
9
6
10
N
OH
1
1
H
N
OCH3
HO8
9a
5a
H 1
2
3
H CO
1
1a
H
1
7
N
H
3
CO
N
5
4
CONH
2
Natural product derived heterocyclic compounds offer
a high degree of structural diversity and thus may lead
to useful therapeutic agents. As a consequence, a wide
range and increasing number of biologically important
heterocyclic compounds have been prepared employing
3
O
DC-81
O
Anthramycin
N
O
(CH
)
3
N
2
O
H
N
H
N
OCH
3
3
H CO
2
solid-phase procedures. It is well known that such
approaches allow the rapid preparation of a large num-
ber of individual compounds in a short time and facili-
O
O
SJG-136
3
Figure 1.
tate their assessment in high-throughput screening.
The pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a
group of potent, naturally occurring, antitumour antibi-
otics produced by various Streptomyces species. These
Recently, Thurston and co-workers reported the solid-
8
4
phase synthesis of pyrrolobenzodiazepines and we have
9
also developed some new solid-phase methodologies.
compounds bind selectively in the minor groove of
DNA while a covalent aminal bond between the electro-
philic C11-position of the PBD and the nucleophilic N2-
However, one of the challenges of the solid-phase com-
binatorialsynthesisofheterocycliccompoundsisdevelop-
ing chemical routes that provide access to the target
compounds without leaving any trace of the linker used
for tethering the starting building blocks to the solid
5
amino group of a guanine base, possibly result in the
biological activity. A number of naturally occurring
and synthetic compounds based on this PBD ring sys-
tem, such as anthramycin, chicamycin, abbeymycin,
10
support. We report here a new traceless approach
for the solid-phase synthesis of pyrrolo[2,1-c][1,4]-
benzodiazepines.
6
DC-81 and its dimers (Fig. 1) have shown varying
degrees of DNA binding affinity and anticancer activity.
For example, a PBD dimer (SJG-136), with an affinity
for Pu-GATC-Py sequences is presently under clinical
The imine containing biologically significant pyrrolo-
benzodiazepine ring system is a reactive moiety and
requires extremely mild conditions for the cleavage from
the resin during its solid-phase synthesis. There are
many methodologies for the preparation of this ring sys-
7
evaluation.
Keywords: Solid-phase synthesis; Traceless; Reductive cleavage; Pyr-
rolo[2,1-c][1,4]benzodiazepines.
1
1
*
Corresponding author. Tel.: +91 4027193157; fax: +91 4027193189/
7160512; e-mail addresses: ahmedkamal@ins.iictnet.com;
ahmedkamal@iict.res.in
tem in solution phase, however, there are very few
1
2
2
reports on its solid-phase synthesis. In the present
investigation a new traceless methodology based on
0
040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.08.090

7668
A. Kamal et al. / Tetrahedron Letters 45 (2004) 7667–7669
i
S
S
SH
O
O
COCl
O
O
O
3
N
3
Br
S
ii, iii
i
R
2
Boc
N
Boc
N
N
Wang Bromo polystyrene 1
6
7
O
8
ii
iv
SH
O
S
3
PPh
N
SH
N
O
H
v
thiol Wang resin 3
R
R
N
N
Scheme 1. Reagents and conditions: (i) CH
3
COSK, DMF, rt 12h; (ii)
O
O
9
LiBH
4
, THF, rt, 8h.
10
Scheme 3. Reagents and conditions: (i) triethylamine, CH
h; (ii) TFA, CH Cl , rt, 1h; (iii) 2-azidobenzoic acid, TBTU, DIPEA,
DMF, rt, 6h; (iv) TPP, anhydrous toluene, rt, 3h; (v) DIBAL-H,
CH Cl
, ꢀ78ꢁC, 12h.
2 2
Cl , 0ꢁC,
6
2
2
COOH
COOH
COCl
i
ii
HN
Boc
N
Boc N
2
2
4
5
6
Scheme 2. Reagents and conditions: (i) Boc anhydride, 2N NaOH,
THF, rt, 2h; (ii) PS-TPP, CCl , reflux, 4h.
Table 1. Yields and EIMS for PBD analogues 10a–h
4
a
+
EIMS [M ]
Product
R
Yields (%)
1
1
1
1
0a
0b
0c
0d
H
7-Me
65
62
20
214
0
reductive cleavage followed by cyclization employing
DIBAL-H has been developed.
8-Me
7-Cl
60214
63
234
(
(
4-Bromomethylphenoxy)methyl
1.4mmol/g, 100–200mesh, 1% DVB) was treated with
polystyrene
1
10e
10f
10g
8-Cl
7-OMe
60234
59
61
230
260
336
potassium thioacetate in DMF. The formation of thio-
ester 2 was indicated by a strong carbonyl stretching
7-OMe, 8-OMe
7-OMe, 8-OBn
1
0h
57
ꢀ
1
vibration at 1680cm in the IR spectrum. The reduc-
a
From initial loading of Wang bromo polystyrene.
tion of 2 using LiBH in THF at room temperature gave
4
the thiol Wang resin 3 (Scheme 1). The precursor Boc
protected proline acid chloride 6 was prepared using
polystyrene triphenylphosphine in CCl (Scheme 2).
4
Acknowledgements
1
3
The resin 3 was linked to the Boc protected proline acid
chloride 6 using triethylamine in dichloromethane to
afford Boc protected proline thioester resin 7. The inter-
mediate, after the deprotection of the Boc group using
TFA, was coupled to the corresponding 2-azidobenzoic
acid in the presence of TBTU and DIPEA to provide the
required resins (8a–h), as indicated by IR spectra that
showed a strong azide stretching vibrations in the range
The authors (K.L.R., V.D. and N.S.) are thankful to
CSIR (New Delhi) for the award of Senior Research
Fellowships.
References and notes
1. (a) Thompson, L. A. Curr. Opin. Chem. Biol. 2000, 4, 324–
ꢀ1
3
37; (b) Lou, B. Drug Discovery Today 2001, 6, 1288–1294.
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between 2080 and 2170cm . Treatment of 8a–h with
excess of PPh in dry toluene at room temperature pro-
2
3
3
1
duced the corresponding resins of iminophosphoranes
9a–h). Finally, the resins 9a–h were treated with DI-
(
BAL-H in dry dichloromethane at ꢀ78ꢁC for 12h to
1
4
afford the desired PBD imines (10a–h) (Scheme 3) in
good yields (57–65%) (Table 1). The thiol form of resin
4
. Thurston, D. E. In Molecular Aspects of Anticancer Drug–
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3 was recovered, and could be reused for the preparation
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In summary, a new traceless solid-phase strategy for
imine-containing pyrrolo[2,1-c][1,4]benzodiazepine sys-
tems has been demonstrated. This is an interesting pro-
cess involving intramolecular aza-Wittig cyclization
through reductive cleavage by employing DIBAL-H.
These reaction conditions are readily amenable for gen-
erating a PBD combinatorial library with diversity in A
and C rings.
4
2
7
8
. Gregson, S. J.; Howard, P. W.; Hartley, J. A.; Brooks, A.
A.; Adams, L. J.; Jenkins, T. C.; Kelland, L. R.; Thurston,
D. E. J. Med. Chem. 2001, 44, 737–748.
. Berry, J. M.; Howard, P. W.; Thurston, D. E. Tetrahedron
Lett. 2000, 41, 6171–6174.

A. Kamal et al. / Tetrahedron Letters 45 (2004) 7667–7669
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14. Preparation of compound 10a: To a suspension of resin 8a
(1.4mmol) in dry toluene, TPP (1.47g, 5.6mmol) was
added and the mixture allowed to stir for 3h at room
temperature to give the resin 9a. This was carefully filtered,
rinsed with toluene and dichloromethane under dry con-
ditions, and dried in vacuo. To the suspension of resin 9a in
dry dichloromethane (10mL) was added DIBAL-H
(2.8mL of 1M solution in hexane, 2.8mmol) dropwise at
ꢀ78ꢁC under nitrogen, and the mixture stirred at the same
temperature for 12h. The reaction was quenched by the
addition of 5% HCl. The resin was filtered and washed with
dichloromethane (3 · 10mL). The combined filtrates were
evaporated to afford the crude product, which was further
purified by column chromatography (silica, ethyl acetate–
hexane, 95:5) to get 10a (182mg, 65% yield from initial
1
0, 1841–1843.
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1
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1
loading of Wang bromo polystyrene). H NMR (200MHz,
6
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3
CDCl ): d = 2.02–2.16 (2H, m), 2.26–2.38 (2H, m), 3.36–
3.94 (3H, m), 7.28–7.38 (2H, m), 7.53 (1H, t, J = 6.69Hz),
7.79 (1H, d, J = 4.46Hz), 8.05 (1H, d, J = 7.43Hz). MS
3. Drewy, D. H.; Coe, D. M.; Poon, S. Med. Res. Rev. 1999,
1
+
26
9, 97–148.
(EI): m/z 200 [M ]; ½aŠD þ343 (c 0.4, CHCl
3
).