The synthesis of chiral Ni II complex of Schiff base of ( S )-2- N -( N -benzylprolyl)aminobenzophenone and 5-amino-4,5- dihydro-3-(2,4,6-trimethylphenyl)isoxazol-5-carboxylic acid

The chiral Ni II complex of Schiff base of ( S )-2- N -( N -benzylprolyl)aminobenzophenone and 5-amino-4,5-dihydro-3-(2,4,6-trimethylphenyl)isoxazol-5-carboxylic acid ( 6 ) was prepared via the cycloaddition of chiral complex of Ni 5 with mesitonitrile oxide 1. The cycloaddition proceeded with complete regioselectivity to provide 5-substituted isoxazolines 6 and 7 . The approach of the dipole takes place predominantly from the less sterically hindered side of dipolarophile 5 , the diastereoisomers were formed in 96:4 ratio. The detailed structure of 6 was established by X-ray analysis.


Introduction
Spiroisoxazolines are heterocyclic nuclei which have stimulated much interest in medicinal and biological chemistry. 1Following the first reports of their herbicidal and plant hormonal activity 2- 4 some naturally occurring spiroisoxazolines have been found useful in other biomedical areas.
7][8][9] More recently it was found that spiroisoxazoline containing SJ755 shows a remarkable integrin antagonist behavior, showing a new application for this class of compounds. 104][15] For example, the reaction of chiral methylene pyrrolidinone 2 and stable mesityl nitrile oxide (1) proceeded under the formation of anti and syn diastereoisomers in the ratio of 67:33, in favor of anti diastereomer.The reaction of nitrile oxide 1 with methylenelacton 3 afforded a 90:10 mixture of cycloadducts in favor of anti diastereomer (Scheme 1). 13On the other hand, cycloaddition of the dipolarophile 4 bearing a bulky silyl group proceeded with high stereoselectivity providing 5,7-trans isoxazoline exclusively. 14,15

Scheme 1
With the goal of developing a simple route to the synthesis of chiral isoxazolinylsubstituted amino acids we focused our attention on the cycloaddition of mesityl nitrile oxide with chiral Ni II complex 5 derived from a Schiff base of (S)-2-N-(Nbenzylprolyl)aminobenzophenone and dehydroalanine.Some years ago Y. N. Belokon et al. described asymmetric synthesis of β-substituted α-amino acids via a chiral Ni II complex 5. 16,17

Results and Discussion
The chiral Ni II complex 5 of Schiff base of (S)-2-N-(N-benzylprolyl)aminobenzophenone and dehydroalanine was prepared according to ref. 18 .Cycloadditions of chiral Ni II complex 5 with mesitonitrile oxide 1 proceeded with complete regioselectivity to provide 5-substituted isoxazolines 6 and 7 in 72% yield.The structures described were characterized via analysis of their respective 1 H-and 13 C-NMR spectra.The ratio of diastereoisomers was determined from quantitative 13 C NMR spectra, by integration of the peaks from spiro-carbon C-19 of the isoxazolines.The cycloaddition proceeded extremely slowly, but the diastereoselectivity was excellent, the diastereoisomers were formed in 96:4 ratio.(Scheme 2).

ARKAT
The major isomer Ni II complex of Schiff base of (S)-2-N-(Nbenzylprolyl)aminobenzophenone and 5-amino-4,5-dihydro-3-(2,4,6-trimethylphenyl)isoxazol-5-carboxylic acid (6) was purified by column chromatography and was identified as 5-substituted isoxazoline by NMR spectroscopic analysis.The stereochemical arrangement and absolute configuration was subsequently confirmed by X-ray-crystallographic analysis (Figure 1 and experimental section).The analysis of the product configuration in 6 indicates that the major cycloadduct 6 arises from the cycloaddition that has occurred on the more sterically accessible face of the dipolarophile 5.A chemical shift of spiro-carbon at C-19 of the isoxazoline ring in 13 C-NMR of both isolated products (101.9ppm for 6 and 100.8 ppm for 7) excludes the possibility that the second isolated product 7 is a regioisomer.
The high diastereoselectivity of the cycloaddition could be due to the fact that the Nbenzylic group of the chiral Ni II complex 5 is probably attached to the Ni atom and can effectively hinder the approach from re face of the alkene.Therefore, the cycloaddition of nitrile oxide 1 arises from the more sterically accessible si face of the exocylic double bond of the dipolarophile 5.

Conclusions
In conclusion, the chiral Ni II complex of Schiff base of (S)-2-N-(Nbenzylprolyl)aminobenzophenone and 5-amino-4,5-dihydro-3-(2,4,6-trimethylphenyl)isoxazol-5-carboxylic acid (6) was prepared via the cycloaddition of chiral complex of Ni 5 with mesitonitrile oxide 1.The cycloaddition proceeded with complete regioselectivity to provide 5substituted isoxazolines 6 and 7 in 72% yield.The analysis of the product configuration in 6 indicates that the major cycloadduct 6 arises from the cycloaddition that has occurred on the more sterically accessible face of the dipolarophile 5. Thus it is steric factors that are responsible for the observed diastereoselectivity (diastereoisomers were formed in 96:4 ratio).

Experimental Section
General Procedures.All starting materials and reagents are commercially available (Fluka, Merck, Avocado or Aldrich) and were used without further purification.Solvents were dried before use.Thin-layer chromatography (TLC glass plates coated with silica 60 F 254 Merck) was used for monitoring of reaction courses; eluent is given in the text.For column chromatography the flash chromatography technique was employed using silica 60 (0.040-0.063 mm, Merck).Melting points (mp) were determined on a Kofler hot plate apparatus and are uncorrected.
The 1 H and 13 C NMR spectra of deuterochloroform solutions were obtained using Varian VXR-300 (300 MHz) instrument, tetramethylsilane (TMS) being the internal reference.

ray Structure Determination of 6. 19
-21The suitable crystals were obtained by slow crystallization from a mixture of ethyl acetate and hexane at room temperature.The crystallographic data were obtained by CAD4 diffractometer.The relevant crystallographic data and structure refinement are given in Table1.The structure was solved by direct methods and refined by anisotropic full-matrix least-squares technique.Perspective view and the numbering of the atoms are depicted in Figure1.The hydrogen atoms were refined isotropically in idealized positions riding on the atom to which they are attached.Crystallographic data for the structure reported in this paper have been deposited with the Cambridge Crystallographic Data Centre.The corresponding deposition number is CCDC 603354.Copies of the data can be obtained free of charge on request to The Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Tel.: +44-1223-336408, Fax: +44-1223 336-033).