A carbene insertion route to β-lactam fused cyclic enediynes

Article abstract of DOI:10.1016/S0040-4039(02)00724-4

A new methodology has been developed for the synthesis of biologically important β-lactam fused enediynes 1 and 2. The key step is the successful insertion of the carbene generated from the diazo enediynes 3 and 4. The result is in sharp contrast to the f

Full text of DOI:10.1016/S0040-4039(02)00724-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 4241–4243
A carbene insertion route to b-lactam fused cyclic enediynes
Amit Basak* and Subrata Mandal
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
Received 21 March 2002; revised 4 April 2002; accepted 12 April 2002
Abstract—A new methodology has been developed for the synthesis of biologically important b-lactam fused enediynes 1 and 2.
The key step is the successful insertion of the carbene generated from the diazo enediynes 3 and 4. The result is in sharp contrast
to the fate of the carbene generated from acyclic enediyne 5 in which case the rearrangement product 6 and the dimer 7 were
obtained. © 2002 Elsevier Science Ltd. All rights reserved.
The successful design of enediynes1,2 requires the incor-
poration of a locking device the purpose of which is to
stabilize the otherwise unstable enediynes. One of the
most common ways of stabilizing a reactive enediyne is
to fuse a small strained ring with the enediyne frame-
work.3 For example, in dynemicin the epoxide ring
serves this purpose.4 Recently, Banfi and Guanti5 as
well as our group6 have independently reported the
synthesis of b-lactam fused enediynes (lactenediynes).
The strained four-membered lactam ring has been
shown to prevent the enediynes from undergoing the
Bergman cyclization7 at room temperature and opening
of the b-lactam ring caused the molecule to undergo the
same under ambient conditions.5 In this paper, we
report a new approach to the synthesis of these
molecules. The salient feature of this new methodology
is that it provides functionality at C-3 of the b-lactam
that can, in principle, be further elaborated or attached
to other entities to boost up its recognition to the target
molecules, namely DNA and proteins.8
to be stable at room temperature, which is not the case
with the aliphatic one which has a half life of 36 h at
30°C.10 Thus, the synthetic manipulation to construct
the b-lactam ring, especially for the nonaromatic one,
should be conducted under mild conditions, preferably
below room temperature and over a short period of
time.
Since there was always a possibility of the carbene
adding to the unsaturation,11 a model study seemed
important before executing the actual chemistry.
Towards this end, the N-homopropargyl-N-propargyl
diazo amide 5 was prepared, which was then subjected
to the rhodium acetate-catalyzed conditions for carbene
generation.12 However, to our dismay, no b- or g-lac-
tam containing products were obtained and instead the
rearrangement product 6 (via addition to the triple
bond) along with the dimer 7 were obtained. Although
this result did dampen our spirits to some extent, we
were still hopeful about the positive outcome in the
actual system because of the rigidity of the cyclic frame-
work of the enediynes and the reported success13 of
carbene insertion to form the oxapenam skeleton
(Scheme 2).
The retrosynthetic analysis of the target enediynes 1
and 2 is shown in Scheme 1. It differs from the earlier
reported ones5,6 in many ways; unlike the previously
reported syntheses, in the present case our strategy was
to first make the cyclic enediynes and then through
appropriate reactions, construct the b-lactam ring. The
benzene fused enediynes have previously9 been shown
Because of the better thermal stability of the benzene
fused enediyne, we began to study the feasibility of the
carbene chemistry in this system first, to be followed by
Scheme 1.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00724-4

4242
A. Basak, S. Mandal / Tetrahedron Letters 43 (2002) 4241–4243
Scheme 2.
non-aromatic enediynes, depending upon the result
obtained. Towards this goal, we synthesized the
enediynyl amide 13 by acylating the known amine
1214 with ethyl malonyl chloride in the presence of
triethylamine. The amide on treatment with p-toluene
sulphonyl azide on potassium carbonate as solid
support15 for 10 min furnished the diazo enediyne 3.
Carrying out the diazo transfer in solution phase
(CH3CN)16 gave a lower yield (50%) and that too
after carrying out the reaction for 36 h! When a solu-
tion of the diazo enediyne 3 was treated with a cata-
lytic amount of rhodium acetate for 30 min, the
starting material disappeared completely and the b-
lactam fused enediynes was obtained as the only
isolable product.17 The yield in the carbene insertion
step was about 50%, the rest being base line decom-
position products (Scheme 3).
sulphonamide.18 Acylation followed by diazo transfer
furnished the diazo enediyne. This on treatment with
rhodium acetate in dichloromethane for 30 min fur-
nished the b-lactam fused enediyne 2 which was
purified by column chromatography. However, the
yield of the carbene insertion step was lower (35%) as
compared to formation of the corresponding aromatic
enediyne (Scheme 4).
In conclusion, we have successfully developed an
alternative route to b-lactam fused enediynes. The
activity, both chemical and biological, of these
molecules are currently under study and will be
reported in due course.
Acknowledgements
These steps were repeated for the synthesis of the
non-aromatic enediyne 2. Thus, the amine 15 was iso-
lated via deprotection of the corresponding
A.B. thanks DST for a research grant. S.M. thanks
CSIR for fellowship.
Scheme 3.

A. Basak, S. Mandal / Tetrahedron Letters 43 (2002) 4241–4243
4243
Scheme 4.
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