1,3-Dipolar cycloadditions of prop-1-ene-1,3-sultone with nitrile oxides/nitrones

Article abstract of DOI:10.1016/S0040-4039(02)02502-9

The scope and limitations of dipolar cycloaddition reactions between nitrile oxides/nitrones and prop-1-ene-1,3-sultone have been investigated. A remarkably high degree of regioselectivity and stereoselectivity was observed. The homochiral sultam 8e was s

Full text of DOI:10.1016/S0040-4039(02)02502-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 395–397
1,3-Dipolar cycloadditions of prop-1-ene-1,3-sultone with nitrile
oxides/nitrones
H. Zhang, W. H. Chan,* Albert W. M. Lee* and W. Y. Wong
Department of Chemistry and Central Laboratory of the Institute of Molecular Technology for Drug Discovery and Synthesis,†
Hong Kong Baptist University, Kowloon Tong, Kowloon, Hong Kong SAR
Received 19 March 2002; revised 21 October 2002; accepted 1 November 2002
Abstract—The scope and limitations of dipolar cycloaddition reactions between nitrile oxides/nitrones and prop-1-ene-1,3-sultone
have been investigated. A remarkably high degree of regioselectivity and stereoselectivity was observed. The homochiral sultam
8e was synthesized in a four-step reaction sequence starting from the substituted isoxazoline 4e obtained from the cycloaddition.
The absolute stereochemistry of this material was assigned by an X-ray crystallographic investigation of the intermediate 7e.
© 2002 Elsevier Science Ltd. All rights reserved.
1,3-Dipolar cycloaddition reactions are among the most
important synthetic manipulations allowing the con-
struction of five-membered ring carbocycles and hetero-
cycles.1 Nitrile oxides and nitrones have been shown to
be effective 1,3-dipoles and they undergo smooth reac-
tions with substituted olefins.2 The 1,3-dipolar reaction
of alkenes with nitrile oxides and nitrones give substi-
tuted isoxazolines and isoxazolidines, respectively. Both
classes of heterocycle are versatile intermediates for the
syntheses of natural products and biologically active
compounds.3
In this paper, we present highly regioselective and
stereoselective 1,3-dipolar cycloaddition reactions of
propene sultone 3 with nitrile oxides 1 and nitrones 2.
To set the stage for our investigation, the requisite
1,3-dipoles were prepared according to literature routes.
Nitrile oxides 1a–f were prepared efficiently from either
the corresponding hydroximoyl chlorides or primary
nitro compounds via base induced dehydrochlorination
and the Mukaiyama reaction, respectively.7,8
The labile nitrile oxides generated in situ were allowed
to react with propene sultone 3 in toluene at room
temperature. Monitored by TLC, nitrile oxides 1a and
1b possessing a sterically undemanding alkyl sub-
stituent underwent a smooth reaction with the dipolar-
ophile giving the corresponding cycloadducts 4a and 4b
in high isolated yields (Table 1, entries 1 and 2).
Equally good yields of adducts were formed between
1c–f and 3 after a longer period of reaction time.
Increased bulkiness of the alkyl or aryl substituents
present in the 1,3-dipoles retarded the rate of the
cycloaddition reaction. In all cases, only one regioiso-
meric substituted isoxazoline 4 was obtained, indicating
high regioselectivity of the transformation.
To extend the scope of the 1,3-dipolar cycloaddition
reactions, the development of new dipolarophiles has
attracted the attention of many scientific investigators.4
In this connection, a,b-unsaturated sultones exemplified
by prop-1-ene-1,3-sultone were developed as effective
dienophiles in Diels–Alder reactions.5 Subsequent
transformations of the d-sultone moiety of the cycload-
ducts allowed the preparation of chiral non-racemic
sultams, which were developed as chiral auxiliaries in
promoting asymmetric synthesis.6 To explore fully the
synthetic utility of propene sultone in cycloaddition
reactions, its reactions as a dipolarophile with nitrile
oxides and nitrones have been investigated.
The 1H NMR spectra of the adducts are consistent with
the structural assignments shown in Scheme 1, which
are compatible with the direction of bond polarization
of both reactants. The cis relationship of the two rings
in all adducts is supported by the coupling constant of
8.8–9.6 Hz observable between H1 and H2. The rela-
tively downfield shift observed for H1 and H4 of 4
* Corresponding author. Tel.: +852-3411-7076; fax: +852-3411-7348;
e-mail: whchan@hkbu.edu.hk
† An area of excellence of the University Grants Committee (Hong
Kong).
0040-4039/03/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02502-9

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H. Zhang et al. / Tetrahedron Letters 44 (2003) 395–397
Table 1. Results of the 1,3-dipolar cycloaddition of prop-1-ene-1,3-sultone, nitrile oxides and nitrones
Entry
Dipole
R1
R2
Temp. (°C)
Time (h)
Product
Yield (%)a
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
2a
2b
2c
CH3
C2H5
(CH3)2CH
(CH3)3C
C6H5
CH3OC6H4
–
–
–
–
–
–
–
–
–
22
22
22
22
22
10
10
24
24
24
24
24
24
24
4a
4b
4c
4d
4e
4f
5a
5b
5c
81
83
74
60
81
78
75
62
86
22
C2H5
(CH3)3C
C6H5
120
120
120
10
11
2d
2e
–
–
120
120
24
24
5d
5f
78
72
a Isolated yield after flash column chromatographic purification.
7e in refluxing formic acid followed by alkali treatment
afforded the chiral sultam 8e in an overall yield of 68%
from 7e. Evidently, the isoxazoline moiety survived
intact under the mild debenzylation conditions. Accord-
favored the regiochemical assignment shown against
the alternative structure. An unambiguous structural
assignment of the products exemplified by 4e was estab-
lished by the X-ray crystallographic analysis as shown
in Figure 1.
To exploit further the synthetic utility of our ‘house-
reagent’, 3 was allowed to react in refluxing toluene
with nitrones 2a–e which are accessible from benzyl
hydroxylamine and the corresponding aldehyde
(Scheme 1).9 Good to excellent yields of the substituted
isoxazolidines 5 were obtained after purification by
flash column chromatography (Table 1, entries 7–11).
In principle, four isomeric products can be formed
between nitrones and an unsymmetrical dipolarophile.
Thus, it was gratifying to observe that the excellent
stereoselectivity and regioselectivity of the 1,3-dipolar
cycloaddition led to the formation of only one product.
A coupling constant of 2.8 Hz observed between H2
and H3 of 5b is compatible with the H cis assignment
for H1, H2 and R2. Again, the structural assignment
was confirmed by X-ray crystallographic analysis as
exemplified by 5c (Fig. 2).
Scheme 1. Formation of isoxazolines and isoxazolidines from
1,3-dipolar cycloaddition.
To demonstrate the synthetic utility of the 1,3-dipolar
cycloadducts 4, their transformations into multifunc-
tional racemic and chiral nonracemic materials were
explored (Scheme 2). For instance, under neutral condi-
tions, the b-hydroxyketone 6f was obtained from Raney
nickel reduction of 4f.10 Adopting the synthetic proto-
col previously established in our laboratory for trans-
forming racemic g-sultones to optically pure g-sultams,
using (S)-(−)-a-phenylethylamine as the chiral resolving
agent, a 1:1 diastereomeric mixture of 7e and 7e% was
prepared in a two-step sequence from 4e.6a Careful
column chromatography resulted in a clear separation
of these two diastereomers. The absolute configuration
of the chiral centers in one of the diastereomers, 7e, was
confirmed by X-ray analysis (Fig. 3). Debenzylation of
Figure 1. Crystal structure of 4e.

H. Zhang et al. / Tetrahedron Letters 44 (2003) 395–397
397
Figure 3. Crystal structure of 7e.
and the AoE scheme of the UGC (AoE/P-10/01) of the
HKSAR is gratefully acknowledged.
Figure 2. Crystal structure of 5c.
References
1. (a) Huisgen, R. In 1,3,-Dipolar Cycloaddition Chemistry;
Padwa, A., Ed.; Wiley: New York, 1984; Vol. 1; (b)
Carruthers, W. In Cycloaddition Reactions in Organic
Synthesis; Pergamon Press: Oxford, 1990.
2. Torssell, K. B. G. Nitrile Oxides, Nitrones and Nitronates
in Organic Synthesis; VCH: New York, 1988.
3. (a) Tice, C. M.; Ganem, B. J. Org. Chem. 1983, 48, 5048;
(b) Vasella, A.; Voeffray, R. Helv. Chim. Acta 1983, 66,
1241; (c) Baggiolini, E. G.; Iacobeli, J. A.; Hennesy, B.
M.; Batcho, A. D.; Sereno, J. F.; Uskokovic, M. R. J.
Org. Chem. 1986, 51, 3098; (d) Kasahara, K.; Iida, H.;
Kibayashi, C. J. Org. Chem. 1989, 54, 2225.
4. (a) deBlas, J.; Carretero, J. C.; Dominguez, E. Tetra-
hedron: Asymmetry 1995, 6, 1035; (b) Louis, C.; Hootele,
C. Tetrahedron: Asymmetry 1995, 6, 2149; (c) Alguacil,
R.; Farina, F.; Martin, M. V. Tetrahedron 1996, 52, 3457.
5. (a) Lee, A. W. M.; Chan, W. H.; Jiang, L.; Poon, K. W.
J. Chem. Soc., Chem. Commun. 1997, 611; (b) Jiang, L.
S.; Chan, W. H.; Lee, A. W. M. Tetrahedron 1999, 55,
2245.
6. (a) Chan, W. H.; Lee, A. W. M.; Jiang, L. S.; Mak, T. C.
M. Tetrahedron: Asymmetry 1997, 8, 2501; (b) Lin, J.;
Chan, W. H.; Lee, A. W. M.; Wong, W. Y. Tetrahedron
1999, 55, 13983; (c) Lin, J.; Chan, W. H.; Lee, A. W. M.;
Wong, W. Y.; Huang, P. Q. Tetrahedron Lett. 2000, 41,
2949.
Scheme 2. Further transformations of cycloadducts: (i) Raney
Ni, H2, 1 atm; (ii) (S)-(−)-a-methylbenzylamine, THF, reflux,
24 h; (iii) POCl3, THF, reflux, 48 h; (iv) HCOOH, rt, 2 h; (v)
KOH/EtOH, rt, 2 h.
ing to our synthetic protocol, in principle, a variety of
multifunctional chiral sultams can be assembled. Their
uses as chiral auxiliaries and chiral catalysts in asym-
metric synthesis are under investigation.
7. Larsen, K. E.; Torssel, K. B. G. Tetrahedron 1984, 40,
2985.
8. Makaiyama, T.; Hoshino, T. J. Am. Chem. Soc. 1960, 82,
5339.
9. (a) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am.
Chem. Soc. 1971, 93, 2897; (b) Tokuyama, H.;
Kuboyama, T.; Amano, A.; Yamashita, T.; Fukuyama,
T. Synthesis 2000, 1299; (c) Polonski, T.; Chimiak, A.
Tetrahedron Lett. 1974, 2453.
Acknowledgements
Financial support from the Faculty Research Commit-
tee of the Hong Kong Baptist University (FRG/99-00/
II-14), the Research Grant Council (HKBU 2024/00P)
10. Curran, D. P. J. Am. Chem. Soc. 1983, 105, 5826.