January 1998
SYNLETT
47
A New Methodology for the Reductive Cyclization of ω-Azido Carbonyl Compounds
Mediated by Tetrathiomolybdate: Application to an Efficient Synthesis of
Pyrrolo[2,1-c][1,4]benzodiazepines
Kandikere R Prabhu, P. S. Sivanand and Srinivasan Chandrsekaran*
Department of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, INDIA.
Received 8 July 1997
Abstract: The ω-azido carbonyl compounds on treatment with
tetrathiomolybdate, 1 led to the formation of 5, 6 and 7 membered cyclic
imines in very good yields under mild conditions. This method is
This methodology was then extended to a successful synthesis of
8a 8b
. The
pyrrolo[2,1-c][1,4]benzodiazepines
and Bzl DC-81,
8a
8b
precursors for
corresponding alcohols
azidobenzoyl)pyrrolidine-carboxaldehydes
Further reaction of these azido aldehydes
and
were prepared by Swern oxidation of the
8
6a
6b
applied successfully to
a
new efficient synthesis of 1,4-
and
to give (2S)-N-(2-
8
7a
7b
benzodiazapinone derivatives and in particular Bzl DC-81.
and
respectively.
7b
7a
and
tetrathiomolybdate at room temparature led to the PBD imines
with
1
8a
and
There is presently considerable interest in DNA-binding ligands such as
pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) as potential antitumour
8b
respectively in very good yields (87% and 90% respectively)
(Scheme) .
1
agents and gene targetted drugs. The PBD class of antitumour
antibiotics are produced biosynthetically by various streptomyces
species. Their antitumour activity is due to covalent binding in the
minor groove of DNA through nucleophillic attack of the N-2 of a
guanine base on the electrophilic C-11 position of the PBD. This aminal
2
linkage thus interfaces with DNA function . Hence the synthesis of this
kind of cyclic imine has attracted considerable attention in the past few
3
years. Various approaches to the synthesis of these imines have been
investigated with varying degrees of success and limitations. The most
promising of these approaches is the aza-Wittig reaction of ω-
4
azidocarbonyl compounds with triphenylphosphine.
In this
communication we report a new approach to a facile synthesis of 5,6
and 7 membered cyclic imines from the corresponding ω-azido carbonyl
compounds mediated by benzyltriethyl-ammonium tetrathiomolybdate,
[PhCH NEt ] MoS , (1) and its application to an efficient synthesis of
pyrrolo[2,1-c] [1,4]benzodiazepines in general and Bzl DC-81 (8b) in
2
3 2
4
Scheme
particular.
In summary we have shown the efficacy of a general method for the
reductive cyclization of ω-azido carbonyl compounds with
tetrathiomolybdate 1 and its application to the synthesis of DNA
interactive PBDs in their imine form under mild and neutral conditions.
Earlier we had shown that tetrathiomolybdate 1 is a useful reagent for
the reductive dimerization of organic thiocyanates and selenocyanates
to the corresponding disulfides and diselenides and also for the
reduction of aryl azides to arylamines. Therefore it was of interest to
5
6
7
Typical experimental procedure:
study the reaction of tetrathiomolybdate 1 with ω-azidocarbonyl
8-Benzyl DC-81, 8b:
7b
(0.075 g, 2mmol)
To a well stirred solution of
compounds and the results are summarized in Table 1.
9
1
in CH CN (3ml) was added tetrathiomolybdate (0.143 g, 0.24 mmol)
3
under argon atmosphere and the mixture was stirred for 10 h at room
temperature (25°C). The solvent was evaporated under vacuum and the
black residue was extracted with CH Cl : ether (1:9 , 20ml x 6). The
2
2
combined extract was filtered through a Celite pad and concentrated
under reduced pressure. The residue was subjected to flash
chromatography on silica gel (eluted with 9:1 , EtOAc/ hexane) to
8b
afford 8-benzyl DC- 81,
as a yellow oil (0.060 g, 90%).
20
4
23
[α]
= +611, (c = 0.0108, CHCl ) [lit. [α]
= +629.6 (c = 0.0108,
D
3
D
1
CHCl )] ; H NMR (90 MHz, CDCl ) δ 7.65 (d, 1H), 7.54 (s 1H) , 7.48-
3
3
7.31 (m, 5 H) , 6.85 (s, 1H), 5.20 (d, J= 2.8 Hz, 2H), 3.97 (s, 3H), 3.90-
3.51 (m, 3H), 2.37- 1.96 (m, 4H).; IR, (neat) 3339, 2932, 2870, 1700,
1626, 1601, 1504, 1454, 1431, 1381, 1261, 1217, 1200, 1178, 1124,
-1
+
+
1091, 1022, 755,735, 698 cm ; MS m/z 337 (M +1), 336 (M ), 245,
217, 91
2a 3a
,
4a
, and were treated with tetrathiomolybdate
When azido ketones
Acknowledgment:
We thank the Department of Science and
1
(1 equiv.) in CH CN (25°C, 10-16 h) the 5 and 6 membered cyclic
3
Technology, New Delhi, for financial support of this project.
2b 3b
4b
imines
,
and
respectively were formed in very good yields.
5a
Similarly the azido aldehyde
cyclization with to form the seven membered cyclic imine
underwent a smooth reductive
5b
1
(67%).