Intramolecular 1,3-dipolar nitrone cycloaddition route to bicyclic fused enediyne

Article abstract of DOI:10.1016/j.tetlet.2005.08.125

Bicyclic isooxazolidinyl enediynes 1 and 2 have been prepared by intramolecular nitrone cycloaddition between the two arms of an acyclic enediyne precursor 13. The reaction is highly regioselective and the two configurational isomers have similar onset te

Full text of DOI:10.1016/j.tetlet.2005.08.125

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 7385–7388
Intramolecular 1,3-dipolar nitrone cycloaddition route to
bicyclic fused enediyne
Amit Basak* and Subhash C. Ghosh
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
Received 9 June 2005; revised 14 August 2005; accepted 23 August 2005
Available online 12 September 2005
Abstract—Bicyclic isooxazolidinyl enediynes 1 and 2 have been prepared by intramolecular nitrone cycloaddition between the two
arms of an acyclic enediyne precursor 13. The reaction is highly regioselective and the two configurational isomers have similar onset
temperatures for BC indicating no influence of bridgehead stereochemistry on the kinetics of cyclization.
Ó 2005 Published by Elsevier Ltd.
Enediynes usually undergo Bergman cyclization1 (cyclo-
aromatization; BC) under ambient conditions when they
are cyclic2 or are capable of forming a pseudo cycle (e.g.,
a H-bonded or metal ion-chelated network).3 The inher-
ent strain in a cyclic framework coupled with the close
proximity of the acetylenic carbons undergoing covalent
connection is responsible for such behavior. Thus, ef-
forts to design enediynes which will undergo BC have
mostly focused on the activation of acyclic systems via
the formation of a cyclic network4 or stabilization of
reactive cyclic systems by fusion to small strained rings.5
In our laboratory over the past few years, we have been
involved in synthesizing enediynes, both acyclic and cyc-
lic and in tuning their activity through various ap-
proaches.6 Bicyclic enediynes are attractive targets and
one can fine tune their activity by controlling the ring
size as well as by changing the state of hybridization
of the ring atoms.7 In this connection, we report here
a one-step approach to the synthesis of bicyclic
isooxazolidine fused enediynes 1 and 2 by a nitrone
cycloaddition route. The reactivity of these enediynes
and attempts to open the isooxazolidine ring are also
described herein.
The dienophile and the dipolarophile in our case are
the alkene and a nitrone, respectively. From the stability
point of view, we decided to synthesize the enediyne 14
to avoid possible complications arising out of tautomer-
ism or conjugation with the alkyne. One can envisage
two possible outcomes of the proposed cycloaddition
that will lead to two regioisomeric isooxazolidines
(Scheme 1).
Before embarking on the synthesis of the nitrone 14, we
wanted to have some idea as to whether the eneyne sys-
tem can act as a 2-electron dienophile or whether the
conjugation with the alkyne moiety would perturb its
electronic nature. In order to clarify this point, the bro-
moalkene 5, made by a DBU-mediated elimination from
the mesylate 10 (Scheme 1) and was treated with the nit-
rone 6 in toluene under reflux. The expected [3+2]-cyclo-
addition indeed took place and we isolated only one
regioisomer, which was assigned the structure 3; its iso-
mer 4 was not observed (Scheme 2).
Thus reassured, we carried out a Sonogashira coupling8
between the bromoalkene 5 and the 4-pentyn-1-ol. PCC
oxidation of the resulting alcohol 12 afforded the unst-
able aldehyde 13 which was immediately converted to
the nitrone 14 by reaction with benzyl hydroxylamine
in methanol. The nitrone exists mainly in the Z-form
In order to study the proposed intramolecular cycload-
dition, we needed to incorporate the proper functional-
ity in the two arms of the enediyne, namely the
2-electron dienophile and the 4-electron dipolarophile.
1
as evidenced from H NMR analysis and was found to
be stable under ambient conditions.
The cycloaddition was then carried out, this time in
refluxing benzene, at a sufficiently dilute concentration
(0.003 M) to minimize the intermolecular reaction. The
reaction was worked up (evaporation of the solvent
Keywords: Enediynes; Nitrone cycloaddition; Regioselective; Bergman
cyclization; Sonogashira coupling.
*
Corresponding author. Tel.: +91 3222283300; fax: +91 3222282252;
e-mail: absk@chem.iitkgp.ernet.in
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.08.125

7386
A. Basak, S. C. Ghosh / Tetrahedron Letters 46 (2005) 7385–7388
OMs
OH
Br
a
b
OH
+
Br
Br
Br
8
10
9
7
c
e
d
OH
H
OH
O
Br
H
5
11
13
12
f
O
O
Ph
Ph
g
N
N
-
O
N
H
H
+
Ph
14
1
2
Scheme 1. Possible outcome of intramolecular cycloaddition and synthesis of isooxazolidine-based enediynes 1 and 2. Reagents: (a) Pd(PPh3)4,
n-BuNH2, 80%; (b) CH3SO2Cl, NEt3, CH2Cl2, 88%; (c) DBU, CH2Cl2, 90%; (d) Pd(PPh3)4, n-BuNH2, 68%; (e) PCC, CH2Cl2, 65%; (f) PhCH2-
NHOH, MeOH, 85%; (g) benzene, reflux, 75%.
O
Ph
N
Br
3
H
H
+
+
O
N
_
N
Ph
Br
O
Ph
6
5
Br
4
(Not obtained)
Scheme 2. Outcome of intermolecular cyclization.
under vacuum) after 6 h and the residue was purified by
chromatography over silica gel. Two products which
were close in their Rf-values in TLC were isolated to-
The overall yield of the cycloaddition was 75% and the
two isomers were produced in a ratio of 1:2.
1
gether as white solid. H NMR analysis confirmed the
The thermal stability of 1 and 2 was then studied using
differential scanning calorimetry.9 Both the isomers
show very similar onset temperatures for BC
(ꢀ200 °C) proving that the configuration (cis or trans)
does not have any effect on the activation barrier to
BC (Fig. 2) in contrast to the cyclic carbonate system
of Nicolaou where stereochemistry did play a major
role.5b Cleavage of the isooxazolidine ring by Zn–
HOAc10 proved to be quite difficult. Although the start-
ing material was consumed, no definite product could
be isolated. The reaction (N–O cleavage) was then
attempted on the simpler and easily available isooxazol-
idine 3. In this case, after the treatment with Zn–HOAc,
and work up, the residue was treated with 4-nitro-
benzenesulfonyl chloride/Et3N in order to protect the
amine. We were able to isolate the elimination product
16, the structure of which was confirmed by NMR and
mass spectral data. The procedure was then repeated
using the bicyclic enediynes, however we could not iso-
late the desired amine in the hydroxyl or eliminated
form. Only the mass spectral data done on a fraction
isolated by HPLC showed a molecular ion peak at m/z
occurrence of cycloaddition (appearance of several dia-
stereotopic hydrogens indicating generation of stereo-
genic centers). However, the spectrum was complicated
by the presence of two isomers and all attempts to sepa-
rate these by conventional chromatography failed. The
compounds could finally be separated by HPLC using
ODS-Diacel column and 90% MeOH/water as the
mobile phase. Both the compounds showed molecular
ion peak at m/z 314 (MH+) showing that they are prod-
ucts from intramolecular cycloaddition. Extensive
decoupling experiments proved that the addition was
highly regioselective, and that the two compounds differ
in the configuration at the bridgehead. The faster run-
ning compound, which is incidentally the minor prod-
uct, was assigned the trans-stereochemistry, 2. This
was based upon a NOESY experiment done on the mix-
ture which showed cross-peaks between the bridge head
hydrogen (Ha) and the methylene (He or Hf) for the
minor isomer (Fig. 1). For the other major isomer, no
such cross-peak could be seen in the NOESY spectrum
and hence it was assigned the cis-stereochemistry, 1.

A. Basak, S. C. Ghosh / Tetrahedron Letters 46 (2005) 7385–7388
7387
Figure 1. NOESY spectrum of mixture of 1 and 2 (assignments for hydrogens b,c/b0,c0 or e,f/e0,f0 or g,h/g0,h0 can be interchanged).
ability of the isooxazolidine ring in lowering the reactiv-
ity of the enediyne core to some extent. Current efforts
are aimed toward finding suitable reaction conditions
for N–O bond cleavage in the enediynes 1 and 2 to
firmly establish this aspect.
In conclusion, we have successfully synthesized two ste-
reoisomeric isooxazolidine fused enediynes by a highly
regioselective 1,3-cycloaddition approach. We are now
trying to explore the possibility of using other dipolaro-
philes to induce the formation of more reactive bicyclic
enediyne systems.
Figure 2. DSC curves of enediynes 1 and 2.
392 (M+), consistent with the structure 17 (Scheme 3).
However, the yield of 17 was so poor (<5%) that we
could not proceed further to check its thermal reactivity.
Thus the effect of fusion of the isooxazolidine ring on
the enediyne core could not be established. A related
10-membered N-containing benzene-fused enediyne
showed an onset temperature of ꢀ110 °C.6j Assuming
that an 11-membered enediyne will have higher onset
temperature, a difference of 90 °C does indicate locking
Selected spectral data: All new compounds were charac-
terized by spectroscopic data. Some of these are men-
1
tioned below (the H and 13C NMR were recorded in
CDCl3 at 200 and 50 MHz, respectively): For com-
pound 1 dH (200 MHz): 1.85–1.78 (1H, m, Hf), 2.13–
2.04 (1H, m, He), 2.30–2.19 (1H, m, Hc), 2.55–2.40
(2H, m, Hg, Hh), 2.99–2.92 (1H, m, Hb), 3.29–3.25

7388
A. Basak, S. C. Ghosh / Tetrahedron Letters 46 (2005) 7385–7388
OH
O
N
N
Ph
Ph
N
H
Ph
Zn/ AcOH
50 oC
SO2Ar
ArSO2Cl
Et3N, DCM, 0 oC
50% (overall)
Br
15
Br
Br
16
3
O
Ph
H
N
o
i) Zn/ AcOH, 50
ii)
C
N
SO2Ar
ArSO2Cl
Et3N, DCM, 0 oC
<5%
17
1/ 2
Scheme 3. Results of isooxazolidine ring openings.
25–31; (c) Lockhart, T. P.; Comita, P. B.; Bergman, R. G.
J. Am. Chem. Soc. 1981, 103, 4082–4090; (d) Lockhart, T.
P.; Comita, P. B.; Bergman, R. G. J. Am. Chem. Soc.
1981, 103, 4091–4096.
(1H, m, Hd), 3.86 (1H, d, J = 13.1 Hz, Hi), 4.07 (1H, d,
J = 13.1 Hz, Hj), 5.14 (1H, dd, J = 6.0, 8.6 Hz, Ha),
7.42–7.13 (9H, m, Ar–H); Mass (EI) m/z: 314 (MH+);
For compound 2 dH (200 MHz): 1.85–1.74 (1H, m,
Hf), 2.21–2.05 (1H, m, He), 2.36–2.24 (1H, m, Hc),
2.60–2.41 (2H, m, Hg and Hh), 2.98–2.90 (1H, m, Hb),
3.30–3.26 (1H, m, Hd), 3.90 (1H, d, J = 13.0 Hz, Hi),
4.03 (1H, d, J = 13.2 Hz, Hj), 5.11 (1H, dd, J = 6.0,
8.2 Hz, Ha), 7.40–7.15 (9H, m, Ar–H); Mass (EI) m/z:
314 (MH+); for 12 dH (200 MHz): 1.94–1.81 (2H, m,
CH2CH2OH), 2.60 (2H, t, J = 6.8 Hz, CH2CH2-
CH2OH), 3.87 (2H, t, J = 6.1 Hz, CH2OH), 5.57 (1H,
dd, J = 2.3, 11.0 Hz, CH@CH2), 5.76 (1H, dd, J = 2.3,
17.5 Hz, CH@CH2), 6.08 (1H, dd, J = 11.0, 17.5 Hz,
CH@CH2), 7.25–7.20 (2H, m, Ar–H), 7.44–7.36 (2H,
m, Ar–H); dC (50 MHz): 16.11, 31.14, 61.50, 79.82,
88.88, 91.43, 93.72, 117.17, 125.35, 126.02, 127.18,
127.33, 127.94, 131.70, 131.76; Mass (EI) m/z: 210
(M+); for 13 dH (200 MHz): 2.79 (4H, s, CH2CH2CHO),
5.58 (1H, dd, J = 2.3, 11.0 Hz, CH@CH2), 5.75 (1H, dd,
J = 2.3, 17.5 Hz, CH@CH2), 6.08 (1H, dd, J = 11.0,
17.5 Hz, CH@CH2), 7.26–7.20 (2H, m, Ar–H), 7.44–
7.34 (2H, m, Ar–H), 9.88 (1H, s, CHO); dC (50 MHz):
12.88, 42.54, 80.10, 88.66, 91.52, 92.03, 117.13, 125.46,
125.62, 127.20, 127.54, 127.90, 131.40, 200.44; Mass
(EI) m/z: 208 (M+); for 14 dH (200 MHz): 2.79–2.67
(4H, m, CH2CH2CH@N), 4.88 (2H, s, CH2Ph), 5.54
(1H, dd, J = 2.0, 10.8 Hz, CH@CH2), 5.71 (1H, dd,
J = 2.0, 17.5 Hz, CH@CH2), 6.02 (1H, dd, J = 11.0,
17.5 Hz, CH@CH2), 6.94 (1H, t, J = 5.3 Hz), 7.46–7.16
(9H, m, Ar–H).
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Acknowledgements
Financial support from the Department of Science and
Technology, Government of India, is gratefully
acknowledged. S.C.G. thanks the Council of Industrial
and Scientific Research, Government of India, for a
fellowship. We thank Dr. S. S. Bag for preliminary
results.
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