Diastereoselective [3+2] cycloadditions of a camphor-derived chiral N- acryloylhydrazide with nitrile oxides: The preparation of optically pure δ2-isoxazolines

Article abstract of DOI:10.1016/S0040-4039(99)02316-3

Reaction of a novel chiral N-acryloylhydrazide with various nitrile oxides proceeded smoothly to afford the cycloadduct with high diastereoselectivity (99:1). The auxiliary can be easily removed from the cycloadducts under mild conditions. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02316-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1453–1456
Diastereoselective [3+2] cycloadditions of a camphor-derived
chiral N-acryloylhydrazide with nitrile oxides: the preparation of
optically pure ∆2-isoxazolines
Kung-Shuo Yang, Jung-Chaing Lain, Chun-Hui Lin and Kwunmin Chen ∗
Department of Chemistry, National Taiwan Normal University, Taipei, Taiwan 116, ROC
Received 20 September 1999; revised 12 November 1999; accepted 22 November 1999
Abstract
Reaction of a novel chiral N-acryloylhydrazide with various nitrile oxides proceeded smoothly to afford the
cycloadduct with high diastereoselectivity (99:1). The auxiliary can be easily removed from the cycloadducts under
mild conditions. © 2000 Elsevier Science Ltd. All rights reserved.
Dipolar cycloadditions constitute one of the most powerful classes of reactions for the construction of
useful and versatile synthetic intermediates in organic synthesis.1 In particular, cycloadditions involving
nitrile oxides as dipoles have been extensively examined and applied towards the total synthesis of
many biologically active natural products.2a–g The development of an efficient route to an optically
active isoxazoline ring system is important because its reaction with an appropriate reagent provides
a strategic alternative to β-hydroxy carbonyls, γ-amino-alcohols, etc.3a–i Among the many strategies, the
reaction of achiral nitrile oxides with chiral acryloyl esters or acrylamides is a conventional approach.
The development of novel chiral auxiliaries that provide a face-shielding capability in cycloaddition of
nitrile oxides is still of great importance.
The Oppolzer camphor sultam 1 is among the most promising chiral auxiliaries presently available
in asymmetric cycloaddition reactions.4 However, moderate to high diastereomeric ratios were obtained
when N-acryloylsultam was reacted with various nitrile oxides.5 The design and synthesis of structural
related auxiliaries for asymmetric synthesis has been rare, especially the functional group modifications
at the C10 position.6 We have recently developed an efficient route for the preparation of a novel
camphor-based auxiliary 2.7 Compound 2 can easily be prepared in 88% overall yield from the known
(+)-ketopinic acid in three steps. Herein, we wish to report the use of 2 as a highly efficient chiral auxiliary
for the asymmetric induction of nitrile oxide cycloadditions.
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02316-3
tetl 16244

1454
Chiral acryloylhydrazide 3 can be easily prepared from 2 (acryloyl chloride, Et3N, CH2Cl2, 0°C, 96%).
Cycloaddition of 3 with benzonitrile oxide 4a in THF provided a disappointingly low diastereomeric
ratio in a total of 92% yield (Table 1, entry 1). The diastereoselectivity was readily ascertained from
1H NMR spectroscopic analysis on the crude product. High diastereoselectivity with excellent chemical
yield was obtained when the reaction was carried out in CH2Cl2 (Table 1, entry 2). The structure of 5a
was characterized by 1H, 13C NMR, HRMS, EA analyses and the absolute stereochemistry was assigned
unambiguously by X-ray crystallographic analysis. The series of examples demonstrate the generality
of this procedure (entries 3–15). High diastereomeric ratios were generally observed regardless of the
1
substituent on the nitrile oxide. Careful examination of H NMR spectra of the cycloadducts 5a–n
indicates that the C2 methine proton (camphor numbering) appears consistently at a range of 4.40–4.62
ppm. On the other hand, the corresponding methine of 6a, 6e and 6l shows up at 4.13, 4.12 and 4.10 ppm,
respectively. This characteristic feature allows the assignment of stereochemistry of the newly generated
stereogenic center of other cycloadducts. The levels of facial selectivity obtained are comparable with
the highest levels of diastereoselectivity reported in [3+2] nitrile oxide cycloadditions.3c,d Sufficient face
shielding of the alkene by the chiral auxiliary might account for the results.
The origin of diastereoselectivity in the nitrile oxide cycloadditions with Oppolzer camphor sultam
has been proposed.5,10 Although the stereochemical outcome of the present study remains unclear, the
preferential formation of configurations may be rationalized as follows. The alkene and the carbonyl
group in 3 may exist as a planar s-cis rotamers. These are believed to be energetically favored over those
of s-trans. However, s-cis acryloylhydrazide may have two low energy rotamers about the C–N bond
which would give rise to two diastereomeric products if a reagent attacks from the same face. Unlike the
planar conformation of chiral camphor sultam with the Cα proton oriented toward the sulfone oxygens,
the rotamer A is likely to be energetically significant over A0 in the transition state. This may be due to
the unfavorable steric interactions between the Cα proton and the N-phenyl substituent in A0. The X-ray
crystal structure of 3 indeed favors this conformer in the solid state. The incorporation of the 20-phenyl
pyrazolidin-30-one system into the camphor skeleton results in the conformation change that causes the
C8 methyl group to effectively shield the approach of dipole from the top face. The major product results
from the ‘bottom side’ attack (Cα re face) of the incoming nitrile oxide.
To complete one cycle of the chiral auxiliary, cycloadducts 5a and 5e were reduced with L-Selectride in
THF at −78°C separately to provide essentially optically pure ∆2-isoxazolines 7a (53%) and 7e (75%).
Excellent enantiomeric excess (99% ee) was obtained by means of optical rotation comparison (7a:
[α]25 −177 (c 0.7, CHCl3); lit.5 [α]25 −179 (c 1.0, CHCl3); 7e: [α]25 −140 (c 1.0, CHCl3); lit.5
D
D
D
[α]25 −141 (c 1.0, CHCl3)). The auxiliary 2 was recovered in high material yield (92 and 89%).
D

1455

1456
In summary, compound 2 has been successfully used as a novel camphor-derived auxiliary for the
[3+2] nitrile oxide cycloadditions to achieve high stereoselection. The efficient synthesis of 2 and the
mild conditions for the removal of the auxiliary make this methodology attractive. Further studies using
this chiral auxiliary to investigate its general utility for asymmetric synthesis are underway.
Acknowledgements
We thank the National Science Council of the Republic of China for financial support. The nitrile
oxides 4i–n provided by Professor C.-F. Yao (National Taiwan Normal University) is gratefully ac-
knowledged. The authors thank Professor C.-H. Ueng (National Taiwan Normal University) and Taipei
Instrumentation Center, College of Science (National Taiwan University) for X-ray crystal determination.
References
1. (a) For a recent review, see: Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98, 863, and references cited therein. (b)
Curran, D. P. Advances in Cycloaddition; JAI: Greenwich, CN, 1988, p. 129. (c) Torssell, K. B. G. Nitrile Oxides, Nitrones
and Nitronates in Organic Synthesis; VCH: New York, 1988. (d) Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410.
2. (a) Zhang, J.; Curran, D. P. J. Chem. Soc., Perkin Trans. 1 1991, 2627. (b) Curran, D. P.; Heffner, T. A. J. Org. Chem. 1990,
55, 4585. (c) Weidner-Wells, M. A.; Fraga-Spano. S. A.; Turchi, I. J. J. Org. Chem. 1998, 63, 6319. (d) Chung, Y. J.; Ryu,
E. J.; Keum, G.; Kim, B. H. Bioorg. Med. Chem. 1996, 4, 209. (e) Kanemasa, S.; Nishiuchi, M.; Wada, E. Tetrahedron
Lett. 1992, 33, 1357. (f) Shimizu, M.; Ukaji, Y.; Inomata, K. Chemistry Lett. 1996, 455. (g) Kanemasa, S.; Nishiuchi, M.;
Kamimura, A.; Hori, K. J. Am. Chem. Soc. 1994, 116, 2324.
3. (a) Akiyama, T.; Okada, K.; Ozaki, S. Tetrahedron Lett. 1992, 33, 5763. (b) Kanemasa, S.; Onimura, K.; Wada, E.; Tanaka,
J. Tetrahedron: Asymmetry 1991, 2, 1185. (c) Curran, D. P.; Jeong, K.-S.; Heffner T. A.; Rebek Jr., J. J. Am. Chem. Soc.
1989, 111, 9238. (d) Stack, J. A.; Heffner, T. A.; Geib, S. J.; Curran, D. P. Tetrahedron 1993, 49, 995. (e) Olsson, T.; Stern,
K.; Sundell, S. J. Org. Chem. 1988, 53, 2468. (f) Oppolzer, W.; Kingma, A. J.; Pillai, S. K. Tetrahedron Lett. 1991, 32, 4893.
(g) Kanemasa, S.; Hayashi, T.; Yamamoto, H.; Wada, E.; Sakurai, T. Bull. Chem. Soc. Jpn. 1991, 64, 3274. (h) Kanemasa,
S.; Onimura, K. Tetrahedron 1992, 48, 8631. (i) Kanemasa, S.; Onimura, K. Tetrahedron 1992, 48, 8645.
4. (a) Liu, J.; Eddings, A.; Wallace, R. H. Tetrahedron Lett. 1997, 38, 6795. (b) Wallace, R. H.; Liu, J.; Zong, K. K. ; Eddings,
A. Tetrahedron Lett. 1997, 38, 6791. (c) Kim, B. H.; Lee, J. Y.; Kim, K.; Whang, D. Tetrahedron: Asymmetry 1991, 2, 27.
(d) Kim, B. H.; Lee, J. Y. Tetrahedron: Asymmetry 1991, 2, 1359. (e) Kim, B. H.; Curran, D. P. Tetrahedron 1993, 49, 293.
(f) Mish, M. R.; Guerra, F. M.; Carreira, E. M. J. Am. Chem. Soc. 1997, 119, 8379.
5. Curran, D. P.; Kim, B. H.; Daugherty, J. ; Heffner, T. A. Tetrahedron Lett. 1988, 29, 3555.
6. For the syntheses of novel camphor-derived chiral auxiliaries and their synthetic applications, see: (a) Chen, C.-J.; Chu,
Y.-Y.; Liao, Y.-Y.; Tsai, Z.-H.; Wang, C.-C.; Chen, K. Tetrahedron Lett. 1999, 40, 1141. (b) Yan, T.-H.; Hung, A.-W.; Lee,
H.-C.; Chang, C.-S.; Liu, W.-H. J. Org. Chem. 1995, 60, 3301. (c) Yan, T.-H.; Chu, V.-V.; Lin, T.-C.; Tseng, W.-H.; Cheng,
T.-W. Tetrahedron Lett. 1991, 32, 5563. (d) Kaye, P. T.; Molema, W. E. J. Chem. Soc., Chem. Commun. 1998, 2479. (e) Ahn,
K. H.; Lee, S.; Lim, A. J. Org. Chem. 1992, 57, 5065.
7. For the synthesis of chiral auxiliary 2 and its asymmetric applications on the Baylis–Hillman reaction, see: Yang, K.-S.;
Chen, K., (submitted).
8. (a) Liu, K.-C.; Shelton, B. R.; Howe, R. K. J. Org. Chem. 1980, 45, 3916. (b) Curran, D. P.; Scanga, S. A.; Fenk, C. J. J.
Org. Chem. 1984, 49, 3474.
9. Yao, C.-F.; Chen W.-C.; Lin, Y.-M. Tetrahedron Lett. 1996, 37, 6339.
10. Kim, K. S.; Kim, B. H.; Park, W. M.; Cho, S. J.; Mhin, B. J. J. Am. Chem. Soc. 1993, 115, 7472.