A catalytic asymmetric 1,3-dipolar cycloaddition of nitrones to allyl alcohol

Article abstract of DOI:10.1246/cl.2001.468

A highly diastereo- and enantioselective 1,3-dipolar cycloaddition of nitrones bearing an amide moiety to allyl alcohol has been realized by using a catalytic amount of diisopropyl (R,R)-tartrate as a chiral auxiliary. Addition of amine N-oxide such as pyridine N-oxide, was crucial to realize a reproducible excellent enantioselectivity up to 98% ee.

Full text of DOI:10.1246/cl.2001.468

468
Chemistry Letters 2001
A Catalytic Asymmetric 1,3-Dipolar Cycloaddition of Nitrones to Allyl Alcohol
Xia Ding, Katsumi Taniguchi, Yutaka Ukaji,* and Katsuhiko Inomata*
Department of Chemical Science, Graduate School of Natural Science and Technology, Kanazawa University,
Kakuma, Kanazawa, Ishikawa 920-1192
(Received February 21, 2001; CL-010147)
A highly diastereo- and enantioselective 1,3-dipolar
solving the precipitate which appeared in the catalytic reaction,
probably as highly aggregated complex of zinc salts containing
(R,R)-DIPT moiety. Since the additive was crucial to realize
high stereoselectivity, a series of reactions of nitrone 2a were car-
ried out in the presence of various kinds of amine N-oxides, or
some other additives.8 As shown in Table 1, the addition of pyri-
dine N-oxide was found to be most effective to produce cis-isox-
azolidine with good enantioselectivity of 64% ee (Entry 4).
cycloaddition of nitrones bearing an amide moiety to allyl alco-
hol has been realized by using a catalytic amount of diisopropyl
(R,R)-tartrate as a chiral auxiliary. Addition of amine N-oxide
such as pyridine N-oxide, was crucial to realize a reproducible
excellent enantioselectivity up to 98% ee.
A 1,3-dipolar cycloaddition is one of the most important
reactions for the construction of 5-membered hetereocyclic com-
pounds. Among the 1,3-dipolar cycloadditions, the asymmetric
one of nitrones to olefins seems to be a useful reaction to prepare
isoxazolidines which are key synthetic intermediates for the syn-
thesis of optically active nitrogen-containing chemicals such as γ-
amino alcohols. Recently, the development of this type of reac-
tion has entered a new stage to control the enantioselectivity in
the addition step.1 For example, several stereocontrolled 1,3-
dipolar cycloadditions to olefins with oxazolidone moiety utiliz-
ing chiral Lewis acids were reported.2,3 As a part of our research
on asymmetric 1,3-dipolar cycloadditions,4 we have reported the
enantioselective 1,3-dipolar cycloaddition of nitrones possessing
a t-butoxycarbonyl or cyano group to allyl alcohol by the use of a
stoichiometric amount of diisopropyl (R,R)-tartrate [(R,R)-DIPT]
as a chiral auxiliary to afford the optically active trans-isoxazo-
lidines.5 Herein, we wish to describe a catalytic enantioselective
1,3-dipolar cycloaddition of nitrones bearing an amide group to
afford the corresponding cis-isoxazolidines, in contrast to the pre-
vious trans-adducts, with high regio-, diastereo- and enantiose-
lectivities.
Firstly, a 1,3-dipolar cycloaddition of a nitrone 2a6 bearing
dibenzylamide moiety to allyl alcohol (1) was investigated using
a stoichiometric amount of (R,R)-DIPT (eq 1). To our surprise,
the corresponding optically active cis-isoxazolidine 3a was
obtained in 85% yield with 50% ee along with a trace amount of
its trans-isomer.
Next, the influence of the substituents on the amide nitro-
gen of nitrone 2 was examined as shown in Table 2. That is,
allyl alcohol (1) was successively treated with 1.6 molar
amounts of diethylzinc (in hexane), a 0.2 molar amount of
(R,R)-DIPT, 1.4 molar amounts of iodine (dissolved in THF), a
1.0 molar amount of pyridine N-oxide in CHCl3, followed by
addition of nitrone 2, and the resulting solution was stirred for
24 h at 0 °C. Almost the same asymmetric inductions were
observed for benzyl, ethyl, or phenyl group on the amide nitro-
gen of nitrones 2 (Entries 1–3), whereas a remarkably high
enantioselectivity was achieved by employing a bulky dialkyl-
amide group bearing secondary alkyl substituents (Entries 4 and
6). Particularly, the reaction of a nitrone 2d6 possessing diiso-
propylamide moiety furnished the corresponding cis-
cycloadduct 3d in an excellent enantioselectivity of 98% ee
(Entry 4). The reaction of an N-benzyl nitrone 2e gave the cis-
cycloadduct 3e diastereoselectively in lower chemical yield, but
still with good enantioselectivity (Entry 5).
The modest enantioselectivity obtained above prompted us
to optimize the conditions toward the catalytic reaction using a
0.2 molar amount of (R,R)-DIPT. In order to obtain the repro-
ducible results, it was required to generate zinc halide species in
situ7 from ethylzinc species and iodine to avoid moisture (eq 2).
Furthermore, the addition of an additive was found to be marked-
ly effective to realize reproducible high enantioselectivity by dis-
Copyright © 2001 The Chemical Society of Japan

Chemistry Letters 2001
469
approach of the nitrone. As a result, the corresponding cis-isoxa-
zolidine was selectively obtained via the exo-transition state.
In conclusion, we could establish an efficient asymmetric
route to the optically active isoxazolidines by the catalytic asym-
metric 1,3-dipolar cycloaddition of nitrones to allyl alcohol. A
complete cis-selectivity was observed for the present reaction, in
striking contrast to the results of the cycloaddition of the nitrone
possessing a t-butoxycarbonyl or cyano group previously report-
ed.5 The ready availability of (R,R)- and (S,S)-DIPT indicates
that this method provides a rich opportunity for preparation of
both enantiomers of isoxazolidines which are versatile synthetic
intermediates for nitrogen-containing chemicals.
The present work was partially supported by Mitsubishi
Chemical Corporation Fund and Grant-in-Aid for Scientific
Research from the Ministry of Education, Science, Sports, and
Culture.
The relative stereochemistry of the cycloadducts 3a,d was
determined by NOE analysis.9 Furthermore, the absolute config-
uration of the cis-isoxazolidine 3a was confirmed to be 3S,5R by
the chemical correlation between its derivative and the stereo-
chemically unambiguous authentic sample. The obtained cis-
cycloadduct 3a (50% ee) was transformed to the compound 4
(Scheme 1), whose specific optical rotation was opposite to that
of the authentic sample 6 derived from 5 which was prepared
from (S)-malic acid5 (Scheme 2). The absolute configurations of
the products 3b–f were tentatively determined to be also 3S,5R.
References and Notes
1
2
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3
Other types of asymmetric 1,3-dipolar cycloaddition of
nitrones: K. B. Jensen, M. Roberson, and K. A. Jørgensen, J.
Org. Chem., 65, 9080 (2000); W. S. Jen, J. J. M. Wiener, and
D. W. C. MacMillan, J. Am. Chem. Soc., 122, 9874 (2000);
K. B. Simonsen, P. Bayón, R. G. Hazell, K. V. Gothelf, and
K. A. Jørgensen, J. Am. Chem. Soc., 121, 3845 (1999); K. B.
Jensen, R. G. Hazell, and K. A. Jørgensen, J. Org. Chem., 64,
2353 (1999); J. P. G. Seerden, M. M. M. Boeren, and H. W.
Scheeren, Tetrahedron, 53, 11843 (1997).
4
a) Y. Yoshida, Y. Ukaji, S. Fujinami, and K. Inomata, Chem.
Lett., 1998, 1023. b) M. Shimizu, Y. Ukaji, and K. Inomata,
Chem. Lett., 1996, 455. c) Y. Ukaji, K. Sada, and K. Inomata,
Chem. Lett., 1993, 1847.
Although the precise mechanism of the asymmetric 1,3-
dipolar cycloaddition reaction is not yet clear, it is possible to
postulate that there is significant steric repulsion between the
amide group of nitrone and the ester moiety in DIPT for the
endo-approach as depicted in Figure 1. This repulsive interac-
tion might disfavor the endo-transition state leading to the
trans-adduct. There is less significant steric interaction in exo-
5
6
7
8
Y. Ukaji, K. Taniguchi, K. Sada, and K. Inomata, Chem. Lett.,
1997, 547.
The stereochemistry of the nitrones 2a,d was determined by
NOE analysis to be Z.
S. E. Denmark and S. P. O’Connor, J. Org. Chem., 62, 3390
(1997).
Ethereal compounds used for the catalytic 1,3-dipolar
cycloaddition of nitrile oxides4b) were not so effective. Amine
N-oxides might be able to coordinate more effectively to zinc
metal like nitrones to avoid the unfavorable aggregation.
NOE established the cis relationship of cycloadducts 3a,d as
shown below.
9