Synthesis of isoxazoline-fused bicyclic enediynes via intramolecular nitrile oxide-alkene cycloaddition

Article abstract of DOI:10.1055/s-2008-1078244

The intramolecular nitrile oxide-alkene cycloaddition has been studied in an enediyne system. It has been shown to be an efficient method for one-step synthesis of isoxazoline-fused bicyclic enediynes. The thermal reactivity of these enediynes is similar

Full text of DOI:10.1055/s-2008-1078244

LETTER
2115
Synthesis of Isoxazoline-Fused Bicyclic Enediynes via Intramolecular Nitrile
Oxide–Alkene Cycloaddition
S
ynthesis of Isoxa
m
z
oline-Fused Bicycl
i
ic Ened
t
iynes Basak,* Runa Pal
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
E-mail: absk@chem.iitkgp.ernet.in
Received 30 April 2008
Dedicated to Professor Sir Jack Baldwin FRS on the occasion of his 70th birthday
respectively, between which an intramolecular [3+2]-cy-
Abstract: The intramolecular nitrile oxide–alkene cycloaddition
has been studied in an enediyne system. It has been shown to be an
efficient method for one-step synthesis of isoxazoline-fused bicy-
clic enediynes. The thermal reactivity of these enediynes is similar
cloaddition reaction may take place to produce products
1A–1D (Scheme 1). We started the synthesis of the cy-
cloaddition precursor by carrying out sequential Sono-
to the isoxazolidine-fused counterparts, thus ruling out any signifi- gashira coupling6 of 1,2-diiodobenzene with THP-
cant effect by the bridgehead double bond.
protected propargyl alcohol and TMS-acetylene to pro-
duce 5. After desilylation, the terminal alkyne carbon was
allylated7 with allyl bromide in the presence of K2CO3 and
copper iodide using acetone as solvent to produce the alk-
ene 7. The alcohol 8 obtained upon deprotection of the
THP ether was converted to the corresponding aldehyde 9
with Dess–Martin reagent.8 The aldehyde was subjected
to Wittig reaction using ethyl (triphenylphosphor-
anylidene)acetate in benzene which resulted in the forma-
tion of a,b-unsaturated ester 10. Base-catalyzed Michael
addition of nitromethane (also acting as solvent) was per-
formed to obtain the corresponding nitro compound 11.
Key word: enediyne, cycloaddition, Bergman cyclization, intra-
molecular, activation
Bicyclic enediynes are attractive targets as the non-ene-
diyne cyclic moiety can be used to modulate their thermal
reactivity.1 Recently,2,3 we have synthesized b-lactam and
isoxazolidine-fused enediynes via nitrone–alkyne and ni-
trone–olefin cycloaddition routes, respectively. We were
curious to know the effect of a bridgehead double bond4
on the thermal behavior of isoxazoline-fused enediyne
system as represented by structures 1A and 1B. These
molecules were synthesized via an intramolecular nitrile
oxide–olefin cycloaddition.5 The synthesis, structure elu-
cidation and reactivity of these molecules are described
herein.
The final cycloaddition was then carried out via the in situ
generated nitrile oxide 2 in refluxing benzene at sufficient
dilution (0.003 M) to minimize intermolecular reactions.
The experimental procedure involved refluxing the reac-
tion mixture comprising of the nitroenediyne 11, p-chlo-
rophenyl isocyanate and triethylamine9 in benzene for 30
hours. Workup and purification yielded two products 1A
and 1B (Scheme 2) which could not be separated by con-
ventional chromatography and were isolated together as a
white solid. The compounds could only be separated by
Towards studying the proposed intramolecular cycloaddi-
tion, we needed to incorporate the proper functionality in
the two arms of the enediyne; namely the 2-electron dipo-
larophile and the 4-electron dipole. The dienophile and
the dipole in our case were an alkene and a nitrile oxide,
COOEt
COOEt
N
N
O
COOEt
O
+
H
H
+
N
–
O
1C
1D
+
COOEt
N
COOEt
N
2
O
+
O
H
H
1B
1A
Scheme 1 Four possible isoxazoline-fused bicyclic enediynes
SYNLETT 2008, No. 14, pp 2115–2118
2
2
.0
8
.2
0
0
8
Advanced online publication: 31.07.2008
DOI: 10.1055/s-2008-1078244; Art ID: D14008ST
© Georg Thieme Verlag Stuttgart · New York

2116
A. Basak, R. Pal
LETTER
OTHP
I
I
OTHP
(i)
(ii)
I
TMS
3
4
5
OTHP
OTHP
(iii)
(iv)
H
6
7
O
H
OH
(v)
(vi)
8
9
EtOOC
COOEt
(viii)
NO2
(vii)
11
10
EtOOC
+
N
–
O
(ix)
2
COOEt
COOEt
H
H
N
N
O
O
+
H
H
1A
1B
Scheme 2 Synthesis of bicyclic isoxazoline-fused enediynes. Reagents and conditions: (i) THP-protected propargyl alcohol, Pd(PPh3)4, CuI,
Et3N, r.t.; (ii) TMS-acetylene, Pd(PPh3)4, CuI, Et3N, r.t.; (iii) KF, methanol; (iv) allyl bromide, K2CO3, CuI, anhyd acetone, reflux; (v) PPTS,
EtOH; (vi) Dess–Martin oxidation; (vii) ethyl (triphenylphosphoranylidene)acetate, anhyd benzene, reflux; (viii) MeNO2, DBU, 0 °C, 2 h;
(ix) p-chlorophenyl isocyanate, Et3N, benzene, 30 h, reflux.
HPLC using ODS-Daicel column and 15% water–MeOH ed. Moreover, Ha showed four cross-peaks in the NOESY
as the mobile phase. The overall yield was 75% and the spectrum corresponding to interactions with Hb, Hc,Hd
two isomers 1A and 1B were produced in a ratio of 1:1.
and He. This allowed us to assign the chemical shifts of the
different protons but not the stereochemistry. Further con-
firmation of the structures came from the HMBC spec-
trum which showed cross-peaks corresponding to Hb and
Hc with C-10 as well as Hd and He with C-1 (Figure 1).
The fact that intramolecular cycloaddition had taken place
was confirmed by the ESI spectrum which showed a peak
at m/z = 330 [M + Na+] for both the enediynes, commen-
surate with the molecular formula of the proposed struc-
1
ture. Between the two possible modes of cyclization, H The distinguishing feature between the structures is the
NMR spectroscopic analysis clearly showed that the cy- difference in chemical shifts for the Hf proton. Energy-
cloaddition had taken place via reaction of the nitrile ox- minimized structures using PM310 (Figure 2) showed the
ide oxygen with the internal carbon of the alkene. This dihedral angle in Hf–C–C=N to be 168° in structure 1A.
was proved by the downfield shift of the Ha proton at d = For structure 1B, the dihedral angle came out to be 18°.
4.98 adjacent to the oxygen atom. For the alternative Thus, C–Hf can interact with the s-antibonding orbital of
mode of cycloaddition which can lead to the structures 1C the C–N bond which induces its downfield shift in struc-
and 1D, an upfield shift of the Ha proton would be expect- ture 1A.
Synlett 2008, No. 14, 2115–2118 © Thieme Stuttgart · New York

LETTER
Synthesis of Isoxazoline-Fused Bicyclic Enediynes
2117
Hg
Hh
Hg
In conclusion, we have successfully synthesized two ste-
reoisomeric isoxazoline-fused enediynes12 by a highly re-
gioselective one-step nitrile oxide–alkene [2+3]-
cycloaddition approach. The structures of the two stereo-
isomeric bicyclic isoxazoline-fused enediynes were fully
characterized by 1H NMR, mass spectroscopy, and
NOESY experiment. The thermal reactivity was studied
for the isoxazoline-fused enediynes and was found to be
similar to that of the isoxazolidine-fused systems.
COOEt
COOEt
Hf
N
Hh
Hb
Hc
Hf
N
3
Hb
Hc
O
O
1
Ha
10
Hd He
Ha
He Hd
1B
1A
Hg
Hh
COOEt
Hg
Hh
COOEt
Hf
N
Hf
N
Acknowledgment
O
A.B. is grateful to DST for funding. R.P. thanks CSIR for a senior
research fellowship. A.B. thanks DST for provision of the 400 MHz
NMR spectrometer sanctioned under the IRPHA program. The au-
thors also thank Professor M. Bhattacharya for assistance with ob-
taining NMR analyses.
O
Hc
Hd
He
Hc
Ha
Hd He
Hd
Hb
Hb
1D
1C
Figure 1
References and Notes
(1) (a) Basak, A.; Shain, J. C.; Khamrai, U. K.; Rudra, K. R.;
Basak, A. J. Chem. Soc., Perkin Trans. 1 2000, 1955.
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K. R.; Nag, S. Bioorg. Med. Chem. Lett. 2000, 10, 1321.
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(3) Basak, A.; Ghosh, S. C. Tetrahedron Lett. 2005, 46, 7385.
(4) (a) Lee, M. D.; Dunne, T. S.; Siegel, M. M.; Chang, C. C.;
Morton, G. O.; Borders, D. B. J. Am. Chem. Soc. 1987, 109,
3464. (b) Zein, N.; McGahren, W. J.; Morton, G. O.;
Ashcroft, J.; Ellested, G. A. J. Am. Chem. Soc. 1989, 111,
6888. (c) Lee, M. D.; Manning, J. K.; Williams, D. R.; Kuck,
N. A.; Testa, R. T.; Borders, D. B. J. Antibiot. 1989, 42,
1070. (d) De Voss, J. J.; Hangeland, J. J.; Townsend, C. A.
J. Am. Chem. Soc. 1990, 112, 4554. (e) De Voss, J. J.;
Townsend, C. A.; Ding, W.-D.; Morton, G. O.; Ellested, G.
A.; Zein, N.; Tabor, A. B.; Schreiber, S. L. J. Am. Chem. Soc.
1990, 112, 9669. (f) Lee, M. D.; Dunne, T. S.; Chang, C. C.;
Siegel, M. M.; Morton, G. M.; Ellested, G. A.; McGahren,
W. J.; Borders, D. B. J. Am. Chem. Soc. 1992, 114, 985.
(5) (a) Carruthers, W. Cycloaddition Reactions in Organic
Synthesis; Pergamon Press: Oxford, 1990, 269.
Figure 2 MM2 structures of 1A and 1B
The onset temperatures for Bergman cyclization (BC) for
these bicyclic isoxazoline-fused enediynes 1A and 1B
were determined using differential scanning calorimetric
(DSC)11 measurements which were recorded without sol-
vent. Both the isomers 1A and 1B showed very close on-
set temperatures for BC at 210 °C and 212 °C,
respectively proving that the bridgehead configuration
does not have any effect on the activation barrier to BC.
The result was compared with the onset temperatures of
isoxazolidine-fused enediynes 12A and 12B (Figure 3).3
While the cis form showed an onset temperature of ca 207
°C, for the trans isomer the onset temperature was found
to be ca 213 °C. These values are very similar to those of
isoxazoline-fused enediynes, thus ruling out the signifi-
cant effect on the activation barrier of BC on fusing of the
isoxazoline ring (an anti-Bredt system) to the enediyne
system as compared to the isoxazolidine ring.
(b) Tufariello, J. J. 1,3-Dipolar Cycloaddition Chemistry,
Vol. 2; Padwa, A., Ed.; Wiley: New York, 1984, 83.
(c) Torssell, K. B. G. Nitrile Oxides, Nitrones and Nitronates
in Organic Synthesis; Wiley: U.S.A., 1988.
(6) (a) Sonogashira, K.; Tohoda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 16, 4467. (b) Takahashi, S.; Kuroyama, Y.;
Sonogashira, K.; Hagihara, N. Synthesis 1980, 627.
(7) For synthesis of allylacetylenes from terminal acetylenes
and allyl halides, see: Bumagin, N. A.; Ponomarev, A. B.;
Beletskaya, I. P. Izv. Akad. Nauk SSSR, Ser. Khim. 1987, 7,
1565.
(8) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7277.
(9) (a) Mukhopadhyay, R.; Datta, S.; Chattopadhyay, P. C.;
Bhattacharjya, A.; Patra, A. Indian J. Chem., Sect. B: Org.
Chem. Incl. Med. Chem. 1996, 35, 1190. (b) Shing, T. K.
M.; Fung, W. C.; Wong, C. H. J. Chem. Soc., Chem.
Commun. 1994, 449.
H
H
O
O
Ph
Ph
N
N
H
H
(10) ArgusLab version 4.0.1, Thomson and Planaria Software
12A
12B
LLC.
(11) (a) Elias, H.-G. Macromolekule, Vol. 1; Huthig & Wepf
Verlag: Basel, 1990, 817. (b) Grubbs, R. H.; Kratz, D.
Chem. Ber. 1993, 126, 149.
Figure 3 Isoxazolidine-fused enediynes
Synlett 2008, No. 14, 2115–2118 © Thieme Stuttgart · New York

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A. Basak, R. Pal
LETTER
(12) Selected Spectroscopic Data: Compound 11: 1H NMR
(400 MHz): d = 1.22 (t, J = 7.0 Hz, 3 H, COOCH2CH3),
2.64–2.76 (m, 1 H, CHCH2COOEt), 3.20–3.22 (m, 2 H,
CCCH2CH), 3.82–3.89 (m, 2 H, CCCHCH2NO2), 4.26 (q,
J = 7.2 Hz, 2 H, COOCH2CH3), 4.55–4.66 (m, 2 H,
7.34–7.36 (m, 2 H, ArH). 13C NMR (100 MHz): d = 14.1,
27.3, 28.7, 29.6, 35.7, 36.3, 61.2, 81.6, 85.0, 88.4, 92.0,
124.9, 127.6, 128.1, 128.2, 129.1, 130.8, 155.5, 169.7. MS
(ESI): m/z = 330 [M + Na+]. HRMS: m/z calcd for
C19H18NO3 [M + H+]: 308.3512; found: 308.3510.
CHCH2NO2), 5.13 (dd, J = 1.6, 10.0 Hz, 1 H, CH2CHCH2),
5.40 (dd, J = 2.0, 17.2 Hz, 1 H, CH2CHCH2), 5.84–5. 90 (m,
1 H, CH2CH=CH2), 7.12–7.19 (m, 2 H, ArH), 7.28–7.38 (m,
2 H, ArH). 13C NMR (100 MHz): d = 0.96, 14.1, 30.1, 31.7,
36.4, 61.2, 81.2, 83.3, 88.6, 90.9, 115.7, 125.1, 126.2, 126.5,
128.2, 128.7, 130.8, 140.7, 170.0. MS (ESI): m/z = 325 [M+].
Compound 1A: 1H NMR (400 MHz): d = 1.29 (t, J = 6.0 Hz,
3 H, COOCH2CH3), 2.68 (dd, J = 7.2, 12.8 Hz, 1 H, Hg), 2.74
(dd, J = 3.2, 14.8 Hz, 1 H, Hd), 2.83 (dd, J = 5.6, 12.8 Hz, 1
H, Hh), 2.91 (dd, J = 1.6, 14.8 Hz, 1 H, He), 3.20 (dd, J = 8.4,
13.2 Hz, 1 H, Hc), 3.60 (dd, J = 2.8, 13.2 Hz, 1 H, Hb), 4.20
(q, J = 5.6 Hz, 2 H, COOCH2CH3), 4.45 (dd, J = 1.6, 5.6 Hz,
1 H, Hf), 4.93–4.97 (m, 1 H, Ha), 7.21–7.29 (m, 2 H, ArH),
Compound 1B: 1H NMR (400 MHz): d = 1.28 (t, J = 5.6 Hz,
3 H, COOCH2CH3), 2.72 (dd, J = 3.4, 14.6 Hz, 1 H, He), 2.91
(dd, J = 3.2, 14.6 Hz, 1 H, Hd), 2.95 (dd, J = 1.6, 14.4 Hz, 1
H, Hg), 3.23 (dd, J = 4.8, 14.4 Hz, 1 H, Hh), 3.30 (dd, J = 7.2,
14.0 Hz, 1 H, Hb), 3.63 (dd, J = 2.8, 14.0 Hz, 1 H, Hc), 3.96
(dd, J = 4.8, 7.2 Hz, 1 H, Hf), 4.20 (q, J = 2.4 Hz, 2 H,
COOCH2CH3), 4.92–4.96 (m, 1 H, Ha), 7.20–7.29 (m, 2 H,
ArH), 7.34–7.36 (m, 2 H, ArH). 13C NMR (100 MHz): d =
14.1, 27.2, 28.5, 29.6, 35.6, 39.9, 60.9, 81.5, 84.9, 88.6, 92.3,
125.0, 127.6, 128.0, 128.3, 129.1, 130.8, 156.3, 171.0. MS
(ESI): m/z 330 [M + Na+]. HRMS: m/z calcd for C19H18NO3
[M + H+]: 308.3512; found: 308.3509.
Synlett 2008, No. 14, 2115–2118 © Thieme Stuttgart · New York

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