Synthesis of DNA-interactive pyrrolo[2,1-c][1,4]benzodiazepines by employing polymer-supported reagents: Preparation of DC-81

Article abstract of DOI:10.1055/s-2004-834821

Polymer-supported reagents have been utilized for the generation of combinatorial library of substituted pyrrolo[2,1-c][1,4]benzodiazepine derivatives that provides a clean and efficient preparation and does not require conventional purification techniques like chromatography. This methodology involves intra molecular aza-Wittig reaction and has been extended for the synthesis of the natural product DC-81 in good overall yields.

Full text of DOI:10.1055/s-2004-834821

LETTER
2533
Synthesis of DNA-Interactive Pyrrolo[2,1-c][1,4]benzodiazepines by
Employing Polymer-Supported Reagents: Preparation of DC-81
Preparationof
D
C
h
-
81 med Kamal,* K. Laxma Reddy, V. Devaiah, N. Shankaraiah
Biotransformation Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad-500 007, India
Fax +91(40)27193189; fax +91(40)27160512; E-mail: ahmedkamal@iict.res.in; E-mail: ahmedkamal@ins.iictnet.com
Received 21 July 2004
10
N
OH
9
H
11
OCH3
Abstract: Polymer-supported reagents have been utilized for the
generation of combinatorial library of substituted pyrrolo[2,1-
c][1,4]benzodiazepine derivatives that provides a clean and effi-
cient preparation and does not require conventional purification
techniques like chromatography. This methodology involves intra
molecular aza-Wittig reaction and has been extended for the synthe-
sis of the natural product DC-81 in good overall yields.
9a
5a
HO
N
H3CO
H
8
H
11a
N
1
7
H3CO
N
2
6
5
4
CONH2
3
O
O
Anthramycin
DC-81
N
(CH2)n
N
O
O
H
N
H
Key words: polymer-supported reagents, combinatorial library,
pyrrolo[2,1-c][1,4] benzodiazepines
N
OCH3
H3CO
O
O
SJG-136 (n = 3); DRG-16 (n = 5)
The strategy for the preparation of libraries of low mole-
cular weight organic molecules for biological screening in
drug discovery programs is a topic of great importance.
Figure 1
Solid-phase as well as solution-phase synthesis has been logues and its dimers4 have been synthesised and evaluat-
employed extensively for the production of chemical li- ed for their DNA binding ability and anticancer activity
braries. In the last few years, the use of solution-phase (Figure 1). Recently, Thurston and co-workers have syn-
methods has received a considerable amount of attention thesised some new PBD dimers, e.g., SJG-136 and DRG-
for the parallel synthesis of low molecular weight com- 16 that show markedly superior in vitro cytotoxic potency
pound libraries. Moreover, in the field of solution phase and interstrand DNA cross-linking reactivity, and SJG-
library generation, the use of polymer-supported reagents 136 is presently under clinical evaluation.5 In the last few
is emerging as a leading strategy that not only gives the years, we have been involved in the structural modifica-
advantage of product isolation and purification of solid- tions of PBD-based compounds6 and also in the develop-
phase chemistry but also provides the benefits of the tra- ment of new synthetic strategies7 including solid-phase
ditional solution-phase reactions.1
synthesis.8 In conjunction with these efforts and to the
best of our knowledge, we herein report for the first time
the synthesis of PBDs by employing polymer-supported
reagents. Moreover, pyrrolo[2,1-c][1,4]benzodiazepine-
5,11-diones (PBD dilactams) are known as non-covalent
interactive minor groove binders. These are also interme-
diates for the synthesis of structurally modified PBD-imi-
nes via oxidation of secondary amines9 or by the reduction
of N-protected dilactams.10 Further, these are known to
exhibit different type of biological properties such as an-
tiphage activity, analgesic antagonist, anti-inflammatory,
psychomotor depressant activity and herbicidal proper-
ties.11
The imine or carbinolamine-containing pyrrolo[2,1-
c][1,4]benzodiazepines are a family of low molecular
weight natural products originally isolated from Strepto-
myces species,2 that are known to exhibit antitumour ac-
tivity. These antibiotics bind selectively in the minor
groove of DNA while a covalent aminal bond is formed
between the electrophilic C11-position of the PBD and the
nucleophilic N2-amino group of a guanine base,3 resulting
in biological activity. The S-configuration at the chiral
C11a-position provides the PBD structure with the neces-
sary right handed twist to fit snugly within the minor
groove. A number of compounds based on DC-81 ana-
COOCH3
COOH
CH2OH
-
+NMe3 BH4
Amberlyst 15
HN
HN
HN
MeOH, r.t., 96%
MeOH, reflux, 95%
3
1
2
Scheme 1
SYNLETT 2004, No. 14, pp 2533–2536
2
2
.1
1
.2
0
0
4
Advanced online publication: 20.10.2004
DOI: 10.1055/s-2004-834821; Art ID: G28104ST
© Georg Thieme Verlag Stuttgart · New York

2534
A. Kamal et al.
LETTER
This synthetic route consists of the coupling of L-prolinol from the PBD imines. In the case of 7g, debenzylation by
(2) with the corresponding 2-azido benzoic acids (4a–g). employing Pd/C provides the naturally occurring DC-81
L-Prolinol has been obtained from commercially available (8, Table 1).16,17 The PBD dilactams have also been ob-
L-proline (1) by its reduction with borohydride exchange tained by polymer-supported reagents employing L-pro-
resin (BER).12a In this way water-soluble prolinol isola- line methyl ester (3)12g instead of L-prolinol to yield PBD
tion becomes easier as this avoids water work-up unlike dilactams 10 (Scheme 1 and Scheme 2).
the conventional methods. Interestingly, in the coupling
In conclusion, we have developed an efficient procedure
reaction of prolinol to the azido benzoic acid by using
for the clean preparation of imine-containing PBDs start-
polymer-supported cyclohexylcarbodiimide,12b,c the ex-
ing from L-proline and azido benzoic acids using poly-
cess of acid and urea by-products can be simply filtered
mer-supported reagents. It is noteworthy in the entire
process, the work-up has been simplified to filtration and
evaporation for all the steps. Application of this protocol
has generated an array of imine-containing PBDs and
from the azido alcohols 5a–g.13 Upon oxidation by
modified Swern procedure using polymer-supported sulf-
oxide,12d compounds 5a–g afford the azido aldehydes
6a–g,14 which, upon intramolecular reductive cyclization
their dilactam derivatives, and further, in this methodolo-
with polymer-supported TPP,12e afford the desired imines
gy all the reagents could be reused thus addressing the
7a–g15 containing the pyrrolobenzodiazepine ring system.
problems of environmental and economical sustainability
(‘green’ chemistry).
The oxidation of 5a–g have also been carried out by em-
ploying polymer-supported perruthenate (PSP)12f as an al-
ternative reagent. The use of polymer-supported sulfoxide
Acknowledgment
and PSP makes this method devoid of the unpleasant
smell of dimethylsulfide and further the formation of
polymer-linked phosphine oxide can be easily filtered out
We are thankful to CSIR, New Delhi for the award of research
fellowship to three of us (K.L.R., V.D. and N.S.).
CH2OH
N3
N3
N
C N
R
R
N
COOH
2, CH2Cl2, r.t., 96–99%
O
4a–g
5a–g
O
O
O
S
N
C N
5
3, CH2Cl2, r.t., 97–99%
(COCl)2, TEA, CH2Cl2,
–50 °C to r.t., 93–96%
CHO
N3
COOCH3
N
N3
O
R
R
N
O
6a–g
9a–g
PPh2
PPh2
CH2Cl2, r.t., 94–97%
CH2Cl2, r.t., 95–99%
O
H
H
N
H
N
R
R
N
N
O
Reference 17
O
7a–g
10a–g
7g
N
HO
H
N
H3CO
O
8 (DC-81)
Scheme 2
Synlett 2004, No. 14, 2533–2536 © Thieme Stuttgart · New York

LETTER
Preparation of DC-81
2535
(6) (a) Kamal, A.; Ramesh, G.; Ramulu, P.; Srinivas, O.;
Table 1 Molecular Ions Observed for PBD Analogues 7a–g, 8 and
10a–g
Rehana, T.; Sheelu, G. Bioorg. Med. Chem. Lett. 2003, 13,
3451. (b) Kamal, A.; Ramulu, P.; Srinivas, O.; Ramesh, G.
Bioorg. Med. Chem. Lett. 2003, 13, 3517. (c) Kamal, A.;
Srinivas, O.; Ramulu, P.; Ramesh, G.; Kumar, P. P. Bioorg.
Med. Chem. Lett. 2003, 13, 3577. (d) Kamal, A.; Ramesh,
G.; Srinivas, O.; Ramulu, P. Bioorg. Med. Chem. Lett. 2004,
14, 471. (e) Kamal, A.; Reddy, P. S. M. M.; Reddy, D. R.
Bioorg. Med. Chem. Lett. 2004, 14, 2669. (f) Kamal, A.;
Reddy, K. L.; Reddy, G. S. K.; Reddy, B. S. N. Tetrahedron
Lett. 2004, 45, 3499.
Entry
7a
R
MS (EI)
200
214
235
230
358
260
336
246
216
230
251
246
374
276
252
H
7b
7-Me
7c
7-Cl
7d
7-OMe
(7) (a) Kamal, A.; Reddy, P. S. M. M.; Reddy, D. R.
Tetrahedron Lett. 2002, 43, 6629. (b) Kamal, A.; Laxman,
E.; Reddy, P. S. M. M. Tetrahedron Lett. 2000, 41, 8631.
(c) Kamal, A.; Laxman, E.; Arifuddin, M. Tetrahedron Lett.
2000, 41, 7743. (d) Kamal, A.; Laxman, E.; Reddy, P. S. M.
M. Synlett 2000, 1476.
(8) (a) Kamal, A.; Reddy, G. S. K.; Raghavan, S. Bioorg. Med.
Chem. Lett. 2001, 11, 387. (b) Kamal, A.; Reddy, G. S. K.;
Reddy, K. L. Tetrahedron Lett. 2001, 42, 6969. (c) Kamal,
A.; Reddy, G. S. K.; Reddy, K. L.; Raghavan, S.
7e
7-Br, 9-Br
7-OMe, 8-OMe
7-OMe, 8-OBn
7-OMe, 8-OH
H
7f
7g
8
10a
10b
10c
10d
10e
10f
10g
7-Me
Tetrahedron Lett. 2002, 43, 2103. (d) Kamal, A.; Reddy, K.
L.; Devaiah, V.; Reddy, G. S. K. Tetrahedron Lett. 2003, 44,
4741. (e) Kamal, A.; Reddy, K. L.; Devaiah, V.;
Shankaraiah, N. Synlett 2004, 1841. (f) Kamal, A.; Reddy,
K. L.; Devaiah, V.; Shankaraiah, N.; Reddy, Y. N.
Tetrahedron Lett. 2004, 45, 7667.
7-Cl
7-OMe
7-Br, 9-Br
7-OMe, 8-OMe
7-OMe, 8-OBn
(9) (a) Thurston, D. E.; Bose, D. S. Chem. Rev. 1994, 94, 433.
(b) Kamal, A.; Howard, P. W.; Reddy, B. S. N.; Reddy, B.
S. P.; Thurston, D. E. Tetrahedron 1997, 53, 3223.
(c) Kamal, A.; Rao, M. V.; Reddy, B. S. N. Khim. Getero.
Soed. (Chem. Heterocycl. Compd.) 1998, 1588.
(10) (a) Hu, W.-P.; Wang, J.-J.; Lin, F.-L.; Lin, Y.-C.; Lin, S.-R.;
Hsu, M.-H. J. Org. Chem. 2001, 66, 2881. (b) Mori, M.;
Uozumi, Y.; Kimura, M.; Ban, Y. Tetrahedron 1986, 42,
3793.
References
(11) (a) Carbateas, P. M. US Patent, 3,732,212, 1973; Chem.
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(12) (a) Joshi, D. D.; Sagar, A. D.; Hilage, N. P.; Salunkhe, M. M.
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M.; Shen, C. M.; Wong, J. Y. Org. Synth., Coll. Vol. VI 1988,
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Chem. Commun. 1967, 629. (d) Liu, Y.; Vederas, J. C. J.
Org. Chem. 1996, 61, 7856. (e) Grieder, A.; Thomas, A. W.
Synthesis 2003, 1707. (f) Hinzen, B.; Ley, S. V. J. Chem.
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(1) (a) Ley, S. V.; Baxendale, I. R.; Bream, R. N.; Jackson, P. S.;
Leach, A. G.; Longbottom, D. A.; Nesi, M.; Scott, J. S.;
Storer, R. I.; Taylor, S. G. J. Chem. Soc., Perkin Trans. 1
2000, 3815. (b) Ley, S. V.; Baxendale, I. R.; Brusotti, G.;
Caldarelli, M.; Massi, A.; Nesi, M. Il Farmaco 2002, 57,
321. (c) Baxendale, I. R.; Ley, S. V.; Piutti, C. Angew.
Chem. Int. Ed. 2002, 41, 2194. (d) Baxendale, I. R.; Lee, A.-
L.; Ley, S. V. Synlett 2001, 9, 1482. (e) Caldarelli, M.;
Habermann, J.; Ley, S. V. J. Chem. Soc., Perkin Trans. 1
1999, 107.
(2) Thurston, D. E. In Molecular Aspects of Anticancer Drug-
DNA Interactions; Neidle, S.; Waring, M. J., Eds.;
Macmillan: London, 1993, 54.
(3) Petrusek, R. L.; Uhlenhopp, E. L.; Duteau, N.; Hurley, L. H.
J. Biol. Chem. 1982, 257, 6207.
(13) PreparationofCompound 5g:N-Cyclohexylcarbodiimide,
N¢-methyl polystyrene (0.66 mmol, 1.30 mmol/g) was added
to a dry reaction vessel. The 2-azido-4-benzoxy-5-methoxy
benzoic acid (4g, 150 mg, 0.50 mmol) in CH2Cl2 (5 mL) was
added to the dry resin and the resulting mixture was stirred
at r.t. After 5 min, prolinol (34 mg, 0.33 mmol) in CH2Cl2 (2
mL) was added and the stirring continued at r.t. for 12 h. The
resin was removed by filtration and washed with CH2Cl2.
Evaporation of the filtrate provided 5g in 98% yield. 1H
NMR (200 MHz, CDCl3): d = 1.65–1.90 (3 H, m), 2.15–2.20
(1 H, m), 3.25–3.36 (2 H, m), 3.69–3.86 (2 H, m), 3.84 (3 H,
s), 4.28–4.37 (1 H, m), 4.75 (1 H, br s), 5.18 (2 H, s), 6.67 (1
H, s), 6.83 (1 H, s), 7.28–7.46 (5 H, m). MS (EI): m/z = 382
[M+].
(4) (a) Thurston, D. E.; Bose, D. S. Chem. Rev. 1994, 94, 433.
(b) Kamal, A.; Rao, M. V.; Laxman, N.; Ramesh, G.; Reddy,
G. S. K. Curr. Med. Chem.: Anti-Cancer Agents 2002, 2,
215.
(5) (a) 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. (b) Gregson, S. J.; Howard,
P. W.; Gullick, D. R.; Hamaguchi, A.; Corcoran, K. E.;
Brooks, N. A.; Hartley, J. A.; Jenkins, T. C.; Patel, S.; Guille,
M. J.; Thruston, D. E. J. Med Chem. 2004, 47, 1161.
Synlett 2004, No. 14, 2533–2536 © Thieme Stuttgart · New York

2536
A. Kamal et al.
LETTER
(14) Preparation of Compound 6g: 6-(Methylsulfinyl)hexa-
noyl methyl polystyrene (0.52 mmol, 2.20 mmol/g) was
swollen in CH2Cl2 (5 mL) at r.t. for 15 min and then cooled
to –50 °C. Oxalyl chloride (0.52 mmol, 66 mg) in CH2Cl2
(1 mL) was added dropwise. After 1 h at that temperature,
azido alcohol (5g, 100 mg, 0.26 mmol) in CH2Cl2 (1 mL)
was added, and the mixture was stirred for 3 h before the
addition of Et3N (0.78 mmol, 79 mg). The mixture was
allowed to warm to r.t. and stirred overnight. The resin was
removed by filtration and washed with CH2Cl2. The filtrate
was washed three times with H2O. The organic phases was
dried (Na2SO4) and evaporated to afford 6g in 95% yield. 1H
NMR (200 MHz, CDCl3): d = 2.14–2.24 (2 H, m), 3.35–3.49
(2 H, m), 3.89 (3 H, s), 4.09–4.15 (2 H, m), 4.60–4.65 (1 H,
m), 5.14–5.20 (2 H, m), 6.69 (1 H, s), 7.32–7.47 (6 H, m),
9.69 (1 H, d, J = 2.33 Hz). MS (EI): m/z = 380 [M+].
(15) Preparation of Compound 7g: Triphenylphosphine
polystyrene (0.9 mmol, 3 mmol/g) was suspended in anhyd
CH2Cl2 (10 mL) and the azido aldehyde (6g, 70 mg, 0.18
mmol) was added, the suspension was stirred for 4 h at r.t.
The resin was removed by filtration and washed with
CH2Cl2. Evaporation of the filtrate to afford 6g in 96% yield.
1H NMR (400 MHz, CDCl3): d = 2.09–2.26 (2 H, m), 3.38–
3.80 (5 H, m), 3.87 (3 H, s), 4.98–5.15 (2 H, m), 6.74 (1 H,
s), 7.08–7.42 (6 H, m), 7.50 (1 H, d, J = 2.97 Hz). MS (EI):
m/z = 336 [M+].
(16) Preparation of Compound 8: To a solution of compound
7g (50 mg, 0.15 mmol) in absolute EtOH (3 mL) was added
10% Pd/C (75 mg) under nitrogen atmosphere. 1,4-Cyclo-
hexadiene (120 mg, 1.50 mmol) was added drop wise to the
solution. The resulting solution was stirred at r.t. for 2.5 h.
The reaction mixture was filtered and evaporated to afford 8
in 91% yield. 1H NMR (400 MHz, CDCl3): d = 2.01–2.10
(2 H, m), 2.30–2.36 (2 H, m), 3.55–3.61 (1 H, m), 3.70–3.74
(1 H, m), 3.79–3.87 (1 H, m), 3.96 (3 H, s), 6.41 (-OH, br s),
6.90 (1 H, s), 7.52 (1 H, s), 7.67 (1 H, d, J = 4.4 Hz). MS
(EI): m/z = 246 [M+]. [a]26D +296 (c 0.02, CHCl3); lit.18
[a]22D +135 (c 0.2, CHCl3).
(17) Thurston, D. E.; Murty, V. S.; Langley, D. R.; Jones, G. B.
Synthesis 1990, 81.
(18) Kyowa Hakko Kogyo, Ltd.; Japanese Patent 58180487,
1983.
Synlett 2004, No. 14, 2533–2536 © Thieme Stuttgart · New York