First total synthesis of (Z)-11-(2-oxopropylidene)-2,3,11,11a-tetrahydro- 1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-5(10H)-one

Article abstract of DOI:10.1080/00397910802638537

The first total synthesis of naturally occurring (Z)-11-(2-oxopropylidene)- 2,3,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-5(10H)-one,a unique cycloanthranilylproline derivative, has been achieved from readily available anthranilic acid in f

Full text of DOI:10.1080/00397910802638537

This article was downloaded by: [University of Miami]
On: 08 January 2015, At: 07:20
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic
Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
First Total Synthesis of (Z)-11-
(2-oxopropylidene)-2,3,11,11a-
tetrahydro-1H-
benzo[e]pyrrolo[1,2-a]
[1,4]diazepin-5(10H)-one
Satish S. More a , D. Shanmughapriya a , Y. Lingam a
& N. B. Patel b
a Custom Pharmaceutical Services, Dr. Reddy's
Laboratories Limited , Hyderabad, India
b Department of Chemistry , Veer Narmad South
Gujarat University , Surat, India
Published online: 27 Apr 2009.
To cite this article: Satish S. More , D. Shanmughapriya , Y. Lingam & N. B. Patel
(2009) First Total Synthesis of (Z)-11-(2-oxopropylidene)-2,3,11,11a-tetrahydro-1H-
benzo[e]pyrrolo[1,2-a][1,4]diazepin-5(10H)-one, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 39:11,
2058-2066, DOI: 10.1080/00397910802638537
To link to this article: http://dx.doi.org/10.1080/00397910802638537
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the
information (the “Content”) contained in the publications on our platform.
However, Taylor & Francis, our agents, and our licensors make no

representations or warranties whatsoever as to the accuracy, completeness,
or suitability for any purpose of the Content. Any opinions and views
expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the
Content should not be relied upon and should be independently verified with
primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages,
and other liabilities whatsoever or howsoever caused arising directly or
indirectly in connection with, in relation to or arising out of the use of the
Content.
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden. Terms & Conditions of access and use can be found at
http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communications1, 39: 2058–2066, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802638537
First Total Synthesis of (Z)-11-
(2-oxopropylidene)-2,3,11,11a-tetrahydro-1H-
benzo[e]pyrrolo[1,2-a][1,4]diazepin-5(10H)-one
Satish S. More,1 D. Shanmughapriya,1 Y. Lingam,1 and N. B. Patel2
1Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Limited,
Hyderabad, India
2Department of Chemistry, Veer Narmad South Gujarat University,
Surat, India
Abstract: The first total synthesis of naturally occurring (Z)-11-(2-oxopropyli-
dene)-2,3,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-5(10H)-one,
a unique cycloanthranilylproline derivative, has been achieved from readily
available anthranilic acid in five steps.
Keywords: Aza Wittig, benzodiazepines, cyclization, cycloanthranilylproline,
a-diazoketone
INTRODUCTION
Benzodiazepine derivatives are privileged scaffolds in medicinal chemis-
try,[1] prompting the development of combinatorial methods for the
synthesis of 1,4-benzodiazepin-2-ones,[2] 1,4-benzodiazepine-2,5-diones,[3]
and related heterocycles.[4,5] A number of benzodiazepines are known to
be potential biologically active compounds, such as the pyrrolo[2,1-c]-
[1,4]benzodiazepine-5,11(10H)-dione moiety, which has been reported to
have antitumor,[6] antiphase, analgesic antagonist, anti-inflammatory,[7]
psychomotor depressant,[8] and anxiolytic activity.[9] The benzodiazepine
is the core structure of various biologically important molecules. The
Received October 8, 2008.
Address correspondence to Satish S. More, Custom Pharmaceutical Services,
Dr. Reddy’s Laboratories Limited, Bollaram Road Miyapur, Hyderabad, India.
E-mail: satishsm@drreddys.com
2058

First Pyrrolobenzadoipine Derivative
2059
Scheme 1. Cycloanthranilylproline and its derivatives.
biological activities of pyrrolo[2,1-c][1,4]benzodiazepine-5,11(10H)-dione
derivatives have attracted considerable interest in their total synthesis and
motivated us to explore this work further to synthesize different naturally
occurring cycloanthranilylproline derivatives.
Cycloanthranilylproline (1) and its derivatives (2–4) were isolated
from field-collected fruit bodies of a myxomycete Fuligo candida, and
their chemical structures are depicted in Scheme 1.[10]
In connection with our ongoing interest in the total synthesis of
benzodiazepine natural products, here we report the total synthesis of
2. To the best of our knowledge, this is the first report of total synthesis
of (Z)-11-(2-oxopropylidene)-2,3,11,11a-tetrahydro-1H-benzo[e]pyrrolo
[1,2-a][1,4]diazepin-5-(10H)-one. We report here a potentially significant
route to 11-alkenyl substituted cycloanthranilylproline, which is not only
concise but also experimentally simple.
RESULTS AND DISCUSSION
In the first instance, anthranilic acid 5 was converted to 2-azido benzoic
acid 6 by diazotization and coupling with sodium azide. 2-Azido benzoic
acid 6 was subjected to reflux using thionyl chloride,[11] and the result-
ing acid chloride was coupled with L-proline to get N-[2-azido benzoyl]
L-proline 7 in good yield.[12] This material was converted to acid chloride
using thionyl chloride in toluene,[12] and the resulting acid chloride was
subjected to condensation with t-butyl acetoacetate in the presence of
magnesium chloride in dichloromethane medium to give tert-butyl deri-
vative 8, which on hydrolysis and decorboxylation in toluene at 80ꢀC
with para toluene sulfonic acid (p-TSA) gave 1-[2-(2-azidobenzoyl)cyclo-
pentyl]-1,3-butanedione 9 in 69% yield. This 1,3-diketo compound 9 was
cyclized by aza-Wittig method[13] by treatment with triphenyl phosphine
in dichloromethane solvent, and the cyclization occurred selectively to

2060
S. S. More et al.
form the seven-membered rings, leading to the final product benzodiaze-
pine 2. During the conversion of compound 7 to compound 8, the acid
chloride racemized during coupling with t-butyl acetoacetate, probably
because of ketene formation, and the compound 8 was obtained as a
racemic mixture. This was confirmed by optical rotation as zero. Because
the tert-butyl ester derivative 8 was obtained as a racemic compound, the
target compound 2 was also obtained as a racemic mixture. The entire
strategy is outlined in Scheme 2.
After achieving the total synthesis of 2 in racemic form, we changed
our strategy to synthesize compound 2 in optically purity. To get com-
pound 2 in optically pure form, the preparation of optically pure 1,3-
diketone 9 intermediate was targeted. The preparation of compound 9
was again started from the same 2-azido benzoic acid 5 by converting
it to compound 6 as in Scheme 2. The acid 6 was then converted to the
respective a-diazo ketone 10 by treating it with ethyl chloroformate
followed by reaction with diazomethane. This diazo ketone 10 was then
condensed with acetaldehyde using the known methodology[14] in the
presence of anhydrous stannous chloride (SnCl2) to give optically pure
1,3-diketone 9 in 65% yield. The diketone was then cyclized by the
aza-Wittig method as per Scheme 2 to give optically pure compound 2.
All the analytical information generated on compound 2 exactly matched
Scheme 2. Reagents and conditions: (i) NaNO2, HCI, ꢁ10ꢀC, CH3COONa;
(ii) SOCl2, toluene, reflux; (iii) L-proline, TEA, rt; (iv) SOCl2, toluene, tert-butyl
acetoacetate, MgCl2, DCM, Hunig’s base; (v) toluene, p-TSA 80ꢀC; and (vi)
PPh3, DCM, 0ꢀC.

First Pyrrolobenzadoipine Derivative
2061
Scheme 3. Reagents and conditions: (i) NaNO2, HCl, NaN3, ꢁ10ꢀC,
CH3COONa, NaNO2; (ii) SOCl2, toluene, reflux; (iii) L-proline, TEA, rt; (iv)
ethyl chloroformate, TEA, CH2N2l; (v) CH3CHO, SnCl2, DCM: rt; and (vi)
PPh3, DCM, 0ꢀC.
that previously reported during the isolation of 2 from a natural
source.[10] The compounds 7, 8, 9, and 10 were obtained as mixtures of
syn and anti rotamers.[15]
To the best of our knowledge, this cyclization of diketo compound 9 to
selective seven-membered ring formation using triphenyl phosphine was a
novel methodology resulting in 11-alkenyl substituted benzodiazepines.
The new strategy of total synthesis is outlined in Scheme 3.
CONCLUSION
In summary, we have achieved the total synthesis of pharmaceutically
important natural product (Z)-11-(2-oxopropylidene)-2,3,11,11a-tetrahy-
dro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-5(10H)-one 2 in racemic as well
as in optically pure form. As part of our continuous research in this area, we
are on the way to total synthesis of other important cycloanthranilylproline
derivatives (3 and 4), which will be communicated in due course.
EXPERIMENTAL
General Methods
1H NMR spectra were determined in CDCl3 and dimethyl sulfoxide
(DMSO-d6) solution on Varian Gemini 200-MHz spectrometers. Proton

2062
S. S. More et al.
chemical shifts (d) are relative to tetramethylsilane (TMS, d 0.00) as
internal standard and are expressed in parts per million (ppm). Spin multi-
plicities are given as s (singlet), d (doublet), t (triplet), and m (multiplet).
Coupling constants (J) are given in hertz. Melting points were determined
using scientific capillary melting-point apparatus and are uncorrected.
Mass spectra were obtained on an HP-5989A mass spectrometer. Thin-
layer chromatography (TLC) was performed on silica-gel plates (SRL
230–400 mesh). All the solvents used were commercially available and
were distilled before use.
2-Azido Benzoic Acid (6)
A solution of anthranilic acid 5 (25.0 g, 0.182 mol) in 6 N aqueous hydro-
chloric acid (625 ml) was cooled to ꢁ5 to ꢁ10ꢀC and added dropwise to a
solution of sodium nitrite (13.3 g, 0.193 mol) in water (200 ml) white
maintaining the temperature at about ꢁ10ꢀC. The clear wine-red solution
thus obtained was stirred at 0–5ꢀC for 1–2 h and added dropwise to a
precooled solution of sodium acetate trihydrate (760 g, 5.58 mol) and
sodium azide (12.5 g, 0.193 mol) in water (1100 ml) at 0–5ꢀC. The reaction
mixture was stirred for 2–3 h at 0–5ꢀC and left to stir overnight at room
temperature. The white precipitate was filtered, washed with water, and
dried in vacuo over phosphorous pentoxide, resulting in 27.38 g (92%
yield) of 2-azidobenzoic acid, which was identified by spectral means
and used without further purification. MS (ES): 344 (2M þ 1), 181
(M þ NH4), IR nmax (KBr) cmꢁ1: 3200–2275, 2105.6, 1693.8, 1268.0;
1H NMR (CDCl3, 200 MHz) d: 7.2–7.4 (m, 2H), 7.5–7.7 (t, 1H, J ¼ 8 Hz),
8–8.2 (d, 1H), J ¼ 9 Hz).
(2S)-1-(2-Azido-benzoyl)-pyrrolidine-2-carboxylic Acid (7)
2-Azidobenzoyl chloride was prepared by heating a solution of 2-
azidobenzoic acid 6 (15.0 g, 0.0917 mol) in thionyl chloride (75.0 ml,
1.03 mol) for 3 h under a nitrogen atmosphere. The excess thionyl chlor-
ide was evaporated under reduced pressure. Dry toluene (2 ꢂ 20 ml) was
added to the residue and evaporated. The crude o-azidobenzoyl chloride
was then used without further purification in the next condensation stage.
A solution of o-azidoaroyl chloride (16.7 g, 0.92 mmol) in dry THF
(140 ml) was added dropwise over a period of 30 min to a solution of
L-proline (13.8 g, 0.12 mol) and triethyl amine (22.34 g, 0.22 mol) in water
(140 ml) cooled to 0ꢀC. The reaction mixture was then stirred at room
temperature for 2 h, and then the organic solvent was removed under

First Pyrrolobenzadoipine Derivative
2063
vacuum. The resultant aqueous solution was acidified until pH ¼ l by
the addition of concentrated hydrochloric acid solution, and the solid
formed was separated by filtration and crystallized from ethyl acetate
to give (2S)-1-(2-azido-benzoyl)-pyrrolidine-2-carboxylic acid 7 as an
off-white powder in 85% yield (20.3 g), a mixture of syn and anti rotamers
(9:2), with mp 160–163ꢀC.
IR nmax (KBr) cmꢁ1: 3450–2630, 2130, 1744, 1590, 1573, 1494, 1456,
1434, 1283, 1227, 862, 775, 762; MS (ES): 521.2 (2M þ 1), 261 (M þ 1);
1H NMR (CDCl3, 200 MHz) d: 1.8–2.4 (m, 7H), 3.28–3.44 (t, 1.69H,
J ¼ 7), 3.72–3.86 (t, 0.31H, J ¼ 7), 4.17–4.26 (dd, 0.18H, J ¼ 8.3,
J ¼ 2.7 Hz), 4.72–4.82 (dd, 0.82H, J ¼ 8.2, J ¼ 3.9), 7.1–7.27 (m, 2H),
7.35 (dd, 1H, J ¼ 7.8, J ¼ 2), 7.45 (dt 1H, J ¼ 7.6, J ¼ 1.6), SOR [c ¼ 1,
methanol] at 24ꢀC: 94.716.
1-[(2S)-1-(2-Azido-benzoyl)-pyrrolidine-2-yl]-2-diazo-ethanone (10)
The solution of potassium hydroxide (KOH; 2.32 g, 0.0414 mol) in anhy-
drous ethanol (50 ml) was added to the round-bottom flask containing
the precooled (0–5ꢀC) solution of N-methyl-N-nitroso-4-toluenesulfona-
mide (12.45 g, 0.0582 mol) in diethyl ether (225 ml) attached to the distil-
lation apparatus. The contents were stirred at 0–5ꢀC for 5–10 min and
then placed into a 60ꢀC oil bath. The yellow color distillate containing
diazo methane was collected, and the distillation was stopped when the
distillate no longer contained the yellow color of diazomethane (approxi-
mately 80 ml). In another round-bottom flask under nitrogen atmos-
phere, ethyl chloroformate (2.29 g, 0.0212 mol) was added to a solution
of 1-(2S)-1-(2-azido benzoyl)-L-proline (5.0 g, 0.0192 mol) and triethyl
amine (2.14 g, 0.0212 mol) in tetrahydrofuran THF, (70 ml) at ꢁ20ꢀC.
The reaction mixture was stirred at ꢁ20ꢀC for 30 min. Then the diazo-
methane solution (0.0211 mol) was added to the reaction mixture at
ꢁ20ꢀC. The reaction mixture was stirred for 1 h at ꢁ20ꢀC and then stirred
for 4–6 h at 0–5ꢀC. The reaction progress was monitored on thin-layer
chromatography (TLC). The reaction was degassed for about 1 h with
nitrogen. Solvents were evaporated, and the residue was dissolved in
dichloromethane. The dichloromethane solution was washed with satu-
rated solution of NaHCO3 and water. The organic phase was dried with
anhydrous Na2SO4 and evaporated, yielding 5.18 g (95%) of
1-[(2S)-1-(2-azido-benzoyl)-pyrrolidine-2-yl]-2-diazo-ethanone 10 as a
pale brown oil, a mixture of syn and anti rotamers (5.2:1).
IR nmax (CHCl3) cmꢁ1: 3670–3200, 3105, 3015, 2883, 2437, 2128,
2110, 1724, 1637, 1630, 1491, 1450, 1419, 1363, 1293, 2126, 1146, 1093,
754, 681, 666, MS (ES): 586.4 (2M þ NH4) ¼ 569.2; (2M þ1), 285.3

2064
S. S. More et al.
(M þ 1); 1H NMR (CDCl3, 200 MHz): d 1.8–2.3 (m, 4H), 3.2–3.5
(m, 0.1.68H), 3.7–3.9 (t, 0.32H), 4.1–4.2 (bd, 0.16H, J ¼ 3.4), 4.6–4.7
(dd, 0.84H, J ¼ 3.7, J ¼ 2.5), 5.2 (bs, 0.17H), 5.9 (bs, 0.83H), 7.2–7.5
(m, 4H); 13C NMR (CDCl3, 200 MHz): 22.4 & 24.33, 29.15 & 31.23,
46.31 & 48.46, 53.102 & 53.329, 63.08 & 64.79, 118.11 & 118.26,
124.74 & 125.01, 127.78 & 128.16, 128.38 & 128.48, 130.45 & 130.55,
135.87, 161, 193.28 & 193.61. SOR [c ¼ 2.9, in CHCl3] at 22.7ꢀC: 153.43.
4-[(2S)-1-(2-Azido-benzoyl)-pyrrolidine-2-yl]-4-hdroxy-but-3-en-2-one (9)
Anhydrous stannous chloride (SnCl2) (1.52 g, 0.0081 mol) was added to a
mixture containing the diazo ketone (2.2 g, 0.0073 mol) in methylene
chloride (10 ml) with stirring at room temperature. Acetaldehyde (0.4 g,
0.009 mol) in methylene chloride (4 ml) was added to this suspension.
After 2–3 h, the reaction progress was monitored with TLC, and anhy-
drous stannous chloride was added if the reaction was incomplete. After
nitrogen evolution had stopped, the reaction was transferred to a separa-
tory funnel, washed with water, and dried over sodium sulfate. Removal
of the solvent left a residue, which was column chromatographed on
silica gel using ethyl acetate–hexane. The yield was 1.52 g (65%) of 9 as
a mixture of syn and anti rotamers (2:1). The diketone was found to be
unstable and was used immediately for the cyclization. However, the
reasonably pure compound was isolated by preparative TLC for spectro-
scopic analysis.
IR nmax (CHCl3) cmꢁ1: 1491, 1450, 1419, 1363, 1293, 2126, 1146,
1
1093, 754, 681, 666; MS (ES): 601.4 (2M þ 1), 301.2 (M þ 1); H NMR
(CDCl3, 200 MHz): d 1.8–2.3 (7H), 3.2–3.5 (m, 1.35, H), 3.7–3.9 (m,
0.65), 4.1–4.2 (dd, J ¼ 8.2, J ¼ 2.4), 4.6–4.7 (m, 0.68H), 5.2 (s, 0.35H),
5.84 (s, 0.65H), 7.0 to 7.6 (m, 4H); 13C NMR (CDCl3, 200 MHz):
24.49 & 24.9, 29.6 & 29.9, 31.6 & 31.8, 48.67 & 48.77, 61.66 & 63.35,
97.18 & 97.47, 118.48, 124.87 & 125.16, 128.1 & 128.28, 130.54 & 130.6,
130.82, 136.19, 167.01, 188.9 & 190.34, 193.5 & 194.7; SOR [c ¼ 3, in
CHCl3] at 22.7ꢀC: 123.75.
(Z)-11-(2-Oxopropylidene)-2,3,11,11a-tetrahydro-1H-benzo[e]pyrrolo-
[1,2-a][1,4]diazepin-5(10H)-one (2)
A solution of the diketone (0.347 g, 0.00116 mol) in drydichloromethane
(20 ml) was added to a solution of triphenyl phosphine (0.318,
0.00121 mol) in the same solvent (20 ml) cooled to 0ꢀC. The solution
was stirred for 8 h at 0–5ꢀC under nitrogen. The reaction progress was

First Pyrrolobenzadoipine Derivative
2065
monitored with TLC. The solvent was removed under reduced pressure,
and the residue was purified by column chromatography using ethyl
acetate=hexane (1:3) to give 0.238 g (81%) of (Z)-11-(2-oxopropyli-
dene)-2,3,11,11a-tetrahydro-1H-benzo[e]pyrrolo[1,2-a] [1,4]diazepin-5(10
H)-one as a white solid. The product was further purified by crystalliza-
tion from toluene=hexane, and analytical results were compared with the
literature report of compound 2.
IR nmax (KBr) cmꢁ1: 3005, 2980, 1635 613, 1592, 1562, 1483, 1454,
1357, 1278, 1261, 1250, 1164, 988, 811, 759, 696, 687; MS (ES): 513.4
(2M þ 1), 257.1 (M þ 1); HR-MS (M þ H): 257.1279 (reported:
257.1289), calculated: 257.1279; HR-MS (MꢁH): 255.1129, calculated
255.1134; 13C NMR: d (CDCl3, 200 MHz): 23.36, 26.97, 29.95, 46.79,
55.25, 91.06, 122.05, 124.28, 131.08, 132.36, 137.04, 158.76, 165.64,
198.29; SOR [c ¼ 3, in CHCl3] at 21.7ꢀC: 729.736; mp: 142–144ꢀC; UV:
kmax (MEOH): 338 nm.
ACKNOWLEDGMENTS
The authors thank Dr. Reddy’s Laboratories Ltd. for supporting this
work and Mr. Abijit Mukherjee and Dr. Vilas Dahanukar of Custom
Pharmaceutical Services for their continuous support and encourage-
ment. The cooperation extended by all colleagues of the analytical
division is gratefully acknowledged.
REFERENCES
1. Evans, B. E.; Rittle, K. E.; Bock, M. G.; Dipardo, R. M.; Freiddinger, R. M.;
Whitter, N. L.; Lundell, G. F.; Veber, D. F.; Anderson, P. S. Methods for
drug discovery: Development of potent, selective, orally effective cholecysto-
kinin antagonists. J. Med. Chem. 1988, 31, 2235–2246.
2. (a) Carlier, P. R.; Zhao, H.; MacQuarrie-Hunter, S. L.; DeGuzman, J. C.;
Hsu, D. C. Enantioselective synthesis of diversely substituted quaternary
1,4-benzodiazepin-2-ones and 1,4-benzodiazepine-2,5-diones. J. Am. Chem.
Soc. 2006, 128, 15215–15220; (b) Ellman, J. A. Design, synthesis, and evalua-
tion of small-molecule libraries. Acc. Chem. Res. 1996, 29, 132–143.
3. Boojamra, C. G.; Burow, K. M.; Thompson, L. A.; Ellman, J. A. Solid-phase
synthesis of 1,4-benzodiazepine-2,5-diones: Library preparation and demon-
stration of synthesis generality. J. Org. Chem. 1997, 62, 1240–1256.
4. Herpin, T. F.; Van Kirk, K. G.; Salvino, J. M.; Yu, S. T.; Labaudiniere, R. F.
Synthesis of a 10,000 member 1,5-benzodiazepine-2-one library by the direc-
ted sorting method. J. Comb. Chem. 2000, 2, 513–521.
5. Wu, Z.; Ercole, F.; FitzGerald, M.; Perera, S.; Riley, P.; Campbell, R.; Pham,
Y.; Rea, P.; Sandanayake, S.; Mathieu, M. N.; Bray, A. M.; Ede, N. J.

2066
S. S. More et al.
Synthesis of tetrahydro-1,4-benzodiazepine-2-ones on hydrophilic polyamide
synphase lanterns. J. Comb. Chem. 2003, 5, 166–171.
6. (a) Gregson, J. S.; Howard, P. W.; Hartley, J. A.; Brooks, N. A.; Adams, L. J.;
Jenkins, T.; Kellan, L. R.; Thurston, D. E. Design, synthesis, and evaluation
of a novel pyrrolobenzodiazepine DNA-interactive agent with highly efficient
cross-linking ability and potent cytotoxicity. J. Med. Chem. 2001, 44, 737–748;
(b) Kamal, A.; Ramulu, P.; Srinivas, O.; Ramesh, G. Synthesis of C-8 metha-
nesulphonate substituted pyrrolobenzodiazepines as potential antitumour
agents. Bioorg. Med. Chem. Lett. 2003, 13, 3517–3519; (c) Kamal, A.; Ramesh,
G; Srinivas, O.; Ramulu, P. Synthesis and antitumour activity of pyrene-
linked pyrrolo [2,1-c] and benzodiazepine hybrids. Bioorg. Med. Chem. Lett.
2004, 14, 471–474; (d) Kamal, A.; Hari Babu, A.; Venkata Ramana, A.;
Venkata Ramana, K.; Vijaya Bharathi, E.; Shiva Kumar, M. Synthesis of
pyrrolo[2,1-c][1,4]benzodiazepines and their conjugates by azido reductive
cyclization strategy as potential DNA-binding agents. Bioorg. Med. Chem.
Lett. 2005, 15, 2621–2623.
7. Carbateas, P. M. 1,2,3,10,11,11A-Hexahydro-5H-pyrrolo(2,1-C)(1,4)benzo-
diazepine-5,11-diones. US Patent 3,732,212, 1973; Chem. Abstr. 1973, 79,
P42570x; US Patent 3,763,183, 1973; Chem. Abstr. 1973, 79, P146567t; US
Patent 3,860,600, 1975; Chem. Abstr. 1975, 83, P58892x.
8. Sterling Drug Inc. (New York, NY). Octahydropyrrido[2,1-c][1,4]benzodiaze-
pines. US Patent 3860600, 1975.
9. (a) Wright, W. B., Jr.; Pyrrolo-benzodiazepines: Method of preparation and
method of use. US Patent 3947408, 1976; (b) Wright, W. B., Jr.; Brabander,
H. J.; Greenblatt, E. N.; Day, I. P.; Hardy, H. A., Jr., Derivatives of 1,2,3,11a-
tetrahydro-5H-pyrrolo[2,1-c][1,4]benzo-diazepine-5,11(10H)-dione as anxio-
lytic agents. J. Med. Chem. 1978, 21, 1087–1089.
10. Nakatani, S.; Yamamoto, Y.; Hayashi, M.; Komiyama, K.; Ishibashi, M.
Cycloanthranilylproline-derived constituents from a myxomycete Fuligo. can-
dida. Chem. Pharm. Bull. 2004, 52 (3), 368–370.
11. Cledera, P.; Avendafio, C.; Menendez, J. C. Rapid analogue synthesis of
C-5 substituted 1,2,3-triazolo-[1,5-a]quinazolines. Tetrahedron. 2002, 58,
9973–9981.
12. Molina, P.; Diaz, I.; Tfirraga, A. Synthesis of pyrrolo [2,1-c][1,4]benzo diaze-
pines via an intramolecular aza-Wittig reaction: Synthesis of the antibiotic
DC-81. Tetrahedron 1995, 51, 5617–5630.
13. Fresneda, P. M.; Molina, P. Application of iminophosphorane-based
methodologies for the synthesis of natural products. Synlett 2004, 1, 1–17.
14. Padwa, A.; Hornbuckle, S. F.; Zhang, Z.; Zhi, L. Synthesis of 1,3-diketones
using a-diazo ketones and aldehydes in the presence of tin(II) chloride. J. Org.
Chem. 1990, 55, 5299–5301.
15. Eguchi, S.; Yamashita, K.; Matsushita, Y.; Kakehi, A. Facile synthesis of
1,4-benzodiazepin-5-one derivatives via intramolecular aza-Wittig reaction:
Application to an efficient synthesis of O-benzyl DC-81. J. Org. Chem.
1995, 60, 4006–4012.