HETEROCYCLES

Paper | Regular issue | Vol. 78, No. 3, 2009, pp. 717-724
Received, 1st October, 2008, Accepted, 10th November, 2008, Published online, 12th November, 2008.
DOI: 10.3987/COM-08-11566

■ One Pot Synthesis of Optically Active 4-Isoxazolines by Asymmetric Addition of Alkynylzinc Reagents to Nitrones Followed by Cyclization

Weilin Wei, Masato Kobayashi, Yutaka Ukaji,* and Katsuhiko Inomata*

Graduate School of Natural Science and Technology, Kanazawa University, Kakuma, Kanazawa, Ishikawa 920-1192, Japan

Abstract

One pot synthesis of optically active 4-isoxazolines was achieved by asymmetric addition of alkynylzinc reagents to nitrones utilizing di(t-butyl) (R,R)-tartrate as a chiral auxiliary followed by cyclization. By addition of dimethylzinc, the cyclization step was accelerated to afford the corresponding 4-isoxazolines with up to 93% ee. Furthermore, a cyclized zinc intermediate could be trapped with formaldehyde to give the corresponding 2,3,4,5-tetrasubstituted 4-isoxazoline with 85% ee.

INTRODUCTION
Compounds bearing a 4-isoxazoline ring are versatile synthetic intermediates¹ and the key components of optically active nitrogen-containing substances, which have potentially high value in chemical and medicinal fields.² One of the most attractive approaches to the synthesis of 4-isoxazolines is 1,3-diplolar cycloaddition of nitrones to acetylenes, however, the method often suffered with poor regioselectivity. Alternative route to 4-isoxazolines is condensation of unsaturated ketones with hydroxylamines.¹ Ring-closure reaction of N-propargyl hydroxylamines catalyzed by zinc or palladium salt also gave 4-isoxazolines.³ Furthermore, direct ring-closure reaction of zinc salt of N-propargyl hydroxylamines, generated in situ by addition of alkynylzinc reagents to nitrones, was reported.⁴ However, it was mentioned that an ester or amide group was necessary in the nitrone for the promotion of the cyclization, and the cyclization took place for a simple nitrone only when an alkyne contained an acetyl group.⁴^b Recently, we developed a catalytic asymmetric addition reaction of alkynylzinc reagents, which were prepared in situ from dimethylzinc and 1-alkynes, to nitrones by utilizing di(t-butyl) (R,R)-tartrate [(R,R)-DTBT] as a chiral auxiliary to afford the corresponding optically active N-(R)-(α-substituted)propargyl hydroxylamines. At the same time, we found an unprecedented phenomenon, enantiomeric enhancement by addition of methylzinc salt of a product-like racemic hydroxylamine as an additive.⁵ During the course of the investigation of the enantiomeric enhancement, a part of the addition product was observed to cyclize giving the corresponding 4-isoxazoline at the later stage of the reaction. Herein, we wish to describe a tandem reaction consisting of a catalytic enantioselective nucleophilic addition of alkynylzinc reagents to nitrones followed by cyclization in the presence of a (R,R)-tartaric acid ester as a chiral auxiliary to give the corresponding (S)-4-isoxazolines with excellent enantioselectivity of up to 93% ee. Furthermore, an intermediary 4-isoxazolin-4-yl zinc species could be trapped by formaldehyde to form a new carbon-carbon bond to afford the corresponding optically active 2,3,4,5-tetrasubstituted 4-isoxazoline.

RESULTS AND DISCUSSION
First an asymmetric addition reaction of alkynylzinc to N-benzyl nitrone 2A followed by cyclization was examined (Table 1); i.e., to a mixture of 0.2 molar amount of bis(methylzinc) salt of (R,R)-DTBT and 0.2 molar amount of methylzinc salt of racemic 4-methoxyphenyl substituted hydroxylamine 4 in toluene, equimolar amounts of dimethylzinc, nitrone 2A and phenyl acetylene (3a) were successively added at 0 °C. After stirring for 18 h at 0 °C, the reaction mixture was warmed up to rt (25 °C) and kept for 24 h to give the cyclized product, (S)-2-benzyl-3,5-diphenyl-2,3-dihydroisoxazole (5Aa), in 51% yield and 90% ee (Entry 1).⁶ In order to improve the cyclization step, 1.0 molar amount of zinc iodide dissolved in THF was added as a promoter after the initial addition reaction. After stirring for 24 h at rt, the corresponding 5Aa was obtained with enantioselectivity of 91% ee, but only in 32% chemical yield (Entry 2). Dimethylzinc was next examined as a promoter instead of zinc iodide. To our delight, the cyclization reaction proceeded smoothly by using 1.6 molar amounts of dimethylzinc to give 5Aa in improved 67% yield with high enantioselectivity (89% ee, Entry 3). When 3.2 molar amounts of dimethylzinc were used, the chemical yield of 5Aa was further increased to 73% with 91% ee (Entry 4). The same reaction was also carried out in ethylbenzene, whereas the chemical yield was not satisfactory in comparison with that in toluene (Entries 4 and 5). A control experiment was carried out in the absence of methylzinc salt of racemic 4-methoxyphenyl substituted hydroxylamine 4. The cyclized product was obtained with poor enantioselectivity of 64% ee (Entry 6), which again confirmed that enantiomeric enhancement could be achieved by employing the racemic product-like additive 4.

Asymmetric addition of several alkynylzinc reagents to other nitrones 2 followed by cyclization was performed under the optimum conditions to furnish the corresponding (S)-2-benzyl-4-isoxazolines 5 with high enantioselectivity (Table 2). The reaction of 2-bromophenyl substituted nitrone 2B with phenyl acetylene (3a) proceeded smoothly to give the desired product 5Ba at rt with 93% ee (Entry 2). 4-Bromophenyl substituted nitrone 2C also gave good enantioselectivity with 86% ee (Entry 3). Other aromatic acetylenes 3b and 3c reacted with 2A to give the corresponding 4-isoxazolines 5Ab and 5Ac with up to 93% ee (Entries 4 and 5). Aliphatic acetylenes 3d and 3e afforded the corresponding 4-isoxazolines 5Ad and 5Ae in both good yields and enantioselectivities (Entries 6 and 7).
Finally, a cyclized zinc intermediate produced by tandem asymmetric addition/cyclization reaction was trapped with formaldehyde at rt to furnish (S)-2-benzyl-3,5-diphenyl-2,3-dihydroisoxazol-4-yl)methanol (6) in decent chemical yield and good chiral induction with 85% ee in the presence of a product-like additive 4 (Scheme 1).⁷
As described above, a catalytic asymmetric addition of alkynylzinc reagents to nitrones followed by cyclization has been developed to provide synthetically useful optically active 4-isoxaolines. By addition of a product-like substrate, the excellent enantioselectivities were realized.⁸ Furthermore, a new carbon-carbon bond formation was achieved by the treatment of the intermediary 4-isoxazolin-4-yl zinc species with formaldehyde to afford the corresponding optically active 2,3,4,5-tetrasubstituted 4- isoxazoline.

References

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6. The absolute stereochemistry of the obtained 4-isoxazolines 5 was determined to be S, because the inversion of the stereochemistry was in principle impossible during the cyclization.
7. Partial racemization might have slightly occurred during this step.
8. The precise mechanism of the asymmetric addition reaction to nitrones 2 is still an open question. Especially, the role of the methylzinc salt of a product-like racemic hydroxylamine 4 in the enantiomeric enhancement remains to be accounted for. The easier assembly of the methylzinc salts of a racemic mixture of the product-like hydroxylamines compared with that of the optically pure (R)- or (S)-product-like hydroxylamine seems to be noteworthy for such the phenomenon.