Synthesis of Spiroisoxazolines by 1,3-Dipolar Cycloaddition

Chemical Institute, PFUK, Mlynska dolina, SK-842 15 Bratislava, Slovak RepublicReceived: 31 August 1996 / Accepted: 3 December 1996 / Published: 8 April 1997Abstract: The cycloaddition of the chiral nitrile oxide 1 to 1-R-substituted 3,3-methylene-5,5-dimethyl-2-pyrrolidinones 2 (where R is H, n-butyl-, 1,1-dimethylethoxycarbonyl-, 1-methylethenyl- and acetyl-)proceeds regioselectively under the formation of spiroisoxazolines, namely 7-R-substituted-6-oxo-8,8-dimethyl-1-oxa-2,7-diazaspiro[4,4]non-2-enes 5 and 6. The asymmetric induction expected by the α-chiralcentre of the nitrile oxide 1 was not very effective, diastereoisomers 5 and 6 were formed in an approximate50:50 ratio. The stereoselectivity of the 1,3-dipolar cycloaddition of the arylnitrile oxide 7 with the chirallactam 3 and the achiral lactone 4 are investigated. The attack of the 1,3-dipole occurred from the less hinderedface of the dipolarophile 3 and 4, giving the major isomer 8 and 10, respectively.Keywords: Lactams, lactones, stereoselectivity of 1,3-dipolar cycloadditions, nitrile oxides.IntroductionThe recent observation of the strong herbicidal activityof spiro cyclic lactams, coupled with the absence oftoxicity to microorganisms [1] and also that somespiroisoxazolines occur naturally (Araplysillins areinhibitors of ATPase [2]) stimulated our interest in thesynthesis of other spirocyclic derivatives. 2-Isoxazolines(4,5-dihydroisoxazoles) are versatile sources of thefunctionality present in natural products [3] and there isrenewed interest in their synthesis via 1,3-dipolarcycloaddition of nitrile oxides to alkenes, particularly inthe factors that influence stereo- and regio-selectivity [4].As a continuation of our effort to utilize heterocycliccompounds as dipolarophiles in 1,3-dipolar cycloadditionreactions [5], we report the cycloaddition of chiral andachiral nitrile oxides with achiral and chiral α-methylene-γ-lactams and lactones (Scheme 1).N Ph O


Introduction
The recent observation of the strong herbicidal activity of spiro cyclic lactams, coupled with the absence of toxicity to microorganisms [1] and also that some spiroisoxazolines occur naturally (Araplysillins are inhibitors of ATPase [2]) stimulated our interest in the synthesis of other spirocyclic derivatives.2-Isoxazolines (4,5-dihydroisoxazoles) are versatile sources of the functionality present in natural products [3] and there is renewed interest in their synthesis via 1,3-dipolar cycloaddition of nitrile oxides to alkenes, particularly in the factors that influence stereo-and regio-selectivity [4].As a continuation of our effort to utilize heterocyclic compounds as dipolarophiles in 1,3-dipolar cycloaddition reactions [5], we report the cycloaddition of chiral and achiral nitrile oxides with achiral and chiral α-methyleneγ-lactams and lactones (Scheme 1).

Results and Discussion
The 1,3-dipolar cycloaddition of the chiral nitrile oxide 1 and achiral α-methylene-γ-lactams 2 affords a mixture of spiroisoxazolines 5 and 6 in 50-65% yield (Scheme 2).The asymmetric induction expected by the α-chiral centre of the nitrile oxide 1 has not been very effective, as has been indicated by AM1 modeling of the respective transition states (The results will be presented elsewhere).While product 5a (R=H) was preferred kinetically (the difference in transition states energies is 0,80 kcal/mol), presumably product 6a was more thermodynamically stable (∆ f H=-0,22 kcal/mol).Indeed, diastereoisomers 5a and 6a were formed in an approximate 50:50 ratio.
Further we envisaged the chiral α-methylene-γ-lactam 3 [7] to be a useful heterocycle for the study of the factors controlling π-facial selectivity since the substituents can be systematically varied.Moreover, the regioselective elaboration of the latent amino functionality of spiroisoxazolines can be used for the preparation of chiral amino acids derivatives.The reaction of chiral αmethylene-γ-lactam 3 and the stable nitrile oxide 7 proceeded with the formation of diastereoisomers 8 and 9 in the ratio of 67 :33, in favour of diastereoisomer 8 (Scheme 3).The attack of the 1,3-dipole occurred from the less hindered face of the dipolarophile 3 giving the major isomer 8. Stereochemical assignments, made on the basis of 13 C NMR, supported the structure of the major isomer 8, arising from the predominant approach of the dipole to the "bottom" of the α-methylene-γ-lactam 3.
The cycloaddition to the achiral α-methylene-γ-lactone 4 [8] proceeded fully analogously.Also in this case the predominant approach of the dipole occurs at the anti-face to the phenyl substituent in the dipolarophile 4. Thus, the reaction of the nitrile oxide 7 with methylenelactone 4 afforded a 90 : 10 mixture of cycloadducts 10 and 1 1 The stereochemical assignments for the cycloadducts 10 and 11 derived from the lactone 4 are based upon 13 C NMR chemical shift correlations.

Conclusion
Evidence for a predictive anti-diastereoselective 1,3dipolar cycloaddition of an arylnitrile oxide to a substituted chiral methylenelactam and an achiral methylenelactone has been presented.

Experimental
General1 H NMR spectra were recorded at 300 MHz on a Varian VXR 300 or at 80 MHz on a Tesla BS 487 at 293 K in CDCl 3 .Spectra were internally referenced to TMS.Peaks are reported in ppm downfield of TMS.Multiplicities are reported as singlet (s), doublet (d), triplet (t), quartet (q), some combination of these, broad (br), or multiplet (m). 13C NMR spectra were recovered at 75.0 MHz on the same spectrometer as 1 H NMR spectra at 293 K in CDCl 3 .NMR analysis of the crude original mixture permitted a determination of ratio of the diastereoisomers.Flash chromatography was carried out on 63-200 µm or 40-60 µm silica gel.Thin layer chromatography was carried out on aluminium backed silica plates containing UV 254 by Lachema and plates were visualized with UV light and Mostaine solution as appropriate.All yields refer to isolated, spectroscopically pure material, and have not been optimized.