Isoxazolidine derivative

The preparation of isoxazolidine derivatives was first reported by Bodforss in 1918 (18CB192). The major synthesis of isoxazolidines involves the cycloaddition of nitrones with alkenes, and isoxazolidines have also enjoyed an increasing use as key intermediates in the synthesis of natural products and other heterocycles (79ACR396, 1892CB1498, 1892CB3291, 1882CB2105). 

Catalytic enantioselective 1,3-dipolar cycloaddition between nitrones with alkenes using a novel heterochiral ytterbium(III) catalyst is reported (Eq. 8.58).91 The desired isoxazolidine derivatives are obtained in excellent yields with excellent diastereo- and enantioselectivities. 

In the overall cycloaddition-rearrangement process [64], the C-3 - C-8a relative stereochemistry of the indolizidinone obtained by rearrangement of the isoxazolidine derives from the cycloaddition step and is not affected during the rearrangement. This allowed the control of two out of three chiral centers in a synthetic protocol for a synthesis of the amphibian alkaloid ( + )-Gephyro-toxin 223AB (Scheme 46) [65c]. 

Table 2.18 Isoxazolidine derivatives 491 a-c obtained from the 1,3-dipolar...

As a kind of special case, the asymmetric 1,3-dipolar reaction of nitrile oxides or nitrones constitutes one of the most useful and convenient methods for preparing isoxazolidine derivatives. 

Over the last years, one of the most studied DCR has been the asymmetric version of the cycloaddition of nitrones with alkenes. This reaction leads to the construction of up to three contiguous asymmetric carbon centers (Scheme 4). The resulting five-membered isoxazolidine derivatives may be converted into amino alcohols, alkaloids, or p-lactams. Several chiral metal complexes have been used as catalysts for this process [13-15, 18-22]. However, the employment of iridium derivatives is very scarce. 

The isoxazolidines derived from aldehydes (17a-b) were converted to eudesmane sesquiterpenes. Thus, quatemization of isoxazolidine (18) was followed by ring expansion via a Stevens rearrangement. 

Figure 2.3, the Michael addition reactions of P-nitrostirenes (10) with 4-pentene-l-magnesium bromide (11a) or 3-butene-1-magnesium bromide (11b) generated the nitronates (12) or (13). Satisfactory to high yields of isoxazolidine derivatives (16) and (18) were obtained when nitronates (12) or (13) were treated, in situ, with ethyl chloroformate and catalytic amount of 4-dimethylaminopyridine (DMAP). 

The 1,3-dipolar cycloaddition of nitrones to alkenes is a useful route to isoxazolidine derivatives, the reductive cleavage of which furnishes a range of compounds such as fi-hydroxy ketones, /S-amino alcohols, etc. [29]. Although Lewis acids are known to promote the cycloaddition [29,30], some nitrones, especially aliphatic nitrones, are unstable under these conditions and lower yields are sometimes obtained. The three-component coupling reaction of benzaldehyde, A/-benzylhydroxylamine, and A-phe-nylmaleimide proceeded smoothly in the presence of a catalytic amount of Sc(OTf)3, to afford the corresponding isoxazolidine derivative in a good yield with high diaster-eoselectivity (Eq. 12) [31]. 

A new route to the 12(S)carba-eudistomin skeleton was developed by T. Kurihara et al. The key substrate for this new route was a 1,2-c/s-2-ethenylazetopyridoindole, which was readily oxidized at 0 °C to afford the corresponding A/-oxide. This A/-oxide spontaneously underwent a [2,3]-Meisenheimer rearrangement to afford the desired oxazepine derivative. Interestingly, when the 1,2-frans-2-ethenylazetopyridoindole was subjected to identical conditions, the [1,2]-Meisenheimer rearrangement occurred exclusively and gave rise to an isoxazolidine derivative. 

At slightly elevated temperatures (40—60 °C) catharanthine. b-oxide (219) undergoes a facile [2,3]-sigmatropic rearrangement with quantitative conversion into the isoxazolidine derivative (220), whose structure was established by the X-ray method. Oxidation at to C-3, followed by Mannich ring-closure, affords an... 

Dipolar cycloadditions between nitrones and alkenes are most useful and convenient for the preparation of isoxazolidine derivatives, which are readily converted to 1,3-amino alcohol equivalents under mild reducing conditions... 

Several examples of the 1,3-dipolar cycloadditions between nitrones and 3-(2-alkenoyl)-l,3-oxazolidin-2-ones using the novel hetero-chiral Yb(III) catalyst are shown in Table 32. In most cases, the desired isoxazolidine derivatives were obtained in excellent yields with excellent diastereo- and enantioselectivities. It is noted that high levels of selectivities were attained at room temperature. Nitrones derived from aromatic and heterocyclic aldehydes gave satisfactory re-... 

The isoxazolidine ring is UV-transparent since it is saturated, and any absorption recorded for isoxazolidine derivatives is due to the substituents.182 Interestingly, the two invertomers 30 and 31 have different intensities, although the peak position is identical.31... 

Dipolar cycloadditions between nitrones and alkenes are most useful and convenient for the preparation of isoxazolidine derivatives, which are readily converted to 1,3-amino alcohol equivalents under mild reducing conditions (Tufariello 1984, Torssell 1988). In spite of the importance of chiral amino alcohol units for the synthesis of biologically important alkaloids, amino acids, 3-lactams, and amino sugars, etc. (for a review see Frederickson 1997), catalytic enantioselective 1,3-dipolar cycloadditions remain relatively unexplored (Seerden et al. 1994, 1995, Gothelf and Jorgensen 1994, Gothelf et al. 1996, Hori et al. 1996, Seebach et al. 1996, Jensen et al. 1997). Catalytic enantioselective... 

Several examples of the 1,3-dipolar cycloadditions between nitrones and 3-(2-alkenoyl)-l,3-oxazolidin-2-ones using the novel hetero-chiral Yb(III) catalyst are shown in table 36. In most cases, the desired isoxazolidine derivatives were obtained in excellent yields with excellent diastereo- and enantioselectivities. It is noted that high levels of selectivities were attained at room temperature. Nitrones derived from aromatic and heterocyclic aldehydes gave satisfactory results, and even in the reaction using the nitrone derived from an aliphatic aldehyde, the cycloaddition proceeded smoothly to give the endo adduct in an excellent enantiomeric excess, albeit low endolexo selectivity was observed. Moreover, it was found that alkenes which could be employed in the present 1,3-dipolar cycloaddition were not limited to 3-(2-alkenoyl)-l,3-oxazolidin-2-one derivatives. When jV-phenylmaleimide was used as a dipolarophile, the desired isoxazolidine derivative was obtained in a 70% yield with endolexo = > 99/1, and the enantiomeric excess of the endo adduct was 70% ee under the standard reaction conditions. It is believed that bidentate coordination [e.g. Yb(III)-3-(2-alkenoyl)-l,3-oxazolidin-2-one] is necessary to obtain... 

Several examples of the 1,3-dipolar cycloaddition of nitrones using the heterochiral Yb(III) catalyst in the absence of MS 4A are shown in table 38. The reactions were performed by adding one equivalent of the corresponding nitrone to the Yb(III) catalyst and then, successively, the same nitrone and a dipolarophile. In all cases, reverse enantiofacial selectivities compared with those obtained in the presence of MS 4A were observed. When N-acryloy 1-1,3-oxazo lidin-2-one was used as a dipolarophile, the desired isoxazolidine derivative was obtained in 88% ee. Other substrates also gave high diastereo- and enantioselectivities in most cases. In the reaction of an aliphatic nitrone, low diastereoselectivity was observed, albeit the endo adduct was obtained in good yield and ee. 

Hydroxyethyl (3-lactam derivative was synthesized using the present reactions (scheme 17). Isoxazolidine derivative 37, prepared via the catalytic enantioselective 1,3-dipolar cycloaddition, was treated with methoxymagnesium iodide (Evans et al. 1985) to give methyl ester 38. Reductive N-O bond cleavage and deprotection of... 

The chemistry of catharanthine is still being vigorously investigated, in connection with the synthesis of vinblastine and its analogues. Details of some of the earlier work have now become available." New work includes the preparation" of a potentially useful keto-ester (220) from an isoxazolidine derivative (219) obtainable from catharanthine. Hydrogenolysis of (219), followed by allylic oxidation and internal Michael addition, affords (220) as a mixture of C-20 epimers (Scheme 38). Other derivatives include" 15jS-hydroxy-15,20-dihydro-... 

The three-component coupling reaction of benzaldehyde, N-benzylhydroxylamine, and iV-phenylmaleimide proceeds smoothly in the presence of a catalytic amount of Sc(OTf)3, to afford the corresponding isoxazolidine derivative in good 3ueld and with high diastereoselectivity (eq 20). ... 

The chiral nickel(II)/Al,A -dioxide complex-catalysed asymmetric 3 + 2-cycloaddition of nitrones to alkylidene malonates produced isoxazolidine derivatives in good yields and excellent diastereo- and enantio-selectivities. (94 6 dr and 99% ee). Asymmetric organocatalysts obtained from (X)-BINAM and L-Q -amino 0 acids catalysed the 3 + 2-cycloaddition of alkyl glyoxylate-derived nitrones with (g)... 

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