Isoxazolidines applications

Various kinds of chiral acyclic nitrones have been devised, and they have been used extensively in 1,3-dipolar cycloaddition reactions, which are documented in recent reviews.63 Typical chiral acyclic nitrones that have been used in asymmetric cycloadditions are illustrated in Scheme 8.15. Several recent applications of these chiral nitrones to organic synthesis are presented here. For example, the addition of the sodium enolate of methyl acetate to IV-benzyl nitrone derived from D-glyceraldehyde affords the 3-substituted isoxazolin-5-one with a high syn selectivity. Further elaboration leads to the preparation of the isoxazolidine nucleoside analog in enantiomerically pure form (Eq. 8.52).78... 

This chapter deals mainly with the 1,3-dipolar cycloaddition reactions of three 1,3-dipoles azomethine ylides, nitrile oxides, and nitrones. These three have been relatively well investigated, and examples of external reagent-mediated stereocontrolled cycloadditions of other 1,3-dipoles are quite limited. Both nitrile oxides and nitrones are 1,3-dipoles whose cycloaddition reactions with alkene dipolarophiles produce 2-isoxazolines and isoxazolidines, their dihydro derivatives. These two heterocycles have long been used as intermediates in a variety of synthetic applications because their rich functionality. When subjected to reductive cleavage of the N—O bonds of these heterocycles, for example, important building blocks such as p-hydroxy ketones (aldols), a,p-unsaturated ketones, y-amino alcohols, and so on are produced (7-12). Stereocontrolled and/or enantiocontrolled cycloadditions of nitrones are the most widely developed (6,13). Examples of enantioselective Lewis acid catalyzed 1,3-dipolar cycloadditions are summarized by J0rgensen in Chapter 12 of this book, and will not be discussed further here. 

The nitrone functionality has also found a number of applications as acceptor of nucleophilic addition, as recently reviewed134. The reaction of nitrone 82 with Id directly affords isoxazolidin-5-ones 83, as shown in equation 51135. 

Mukai et al. (36,37) applied the chiral tricarbonyl(r 6-arene)chromium(0)-derived nitrone 24b in 1,3-dipolar cycloadditions with various alkenes, such as styrene 25 (Scheme 12.11). The analogous nonmetallic nitrone 24a was used in a reference reaction with 25, giving the isoxazolidine 26a with an endo/exo ratio of 82 18. By the application of nitrone 24b in the 1,3-dipolar cycloaddition with 25, the endo/exo-selectivity changed significantly to give exo-26b as the only observable product. The tricarbonylchromium moiety effectively shielded one face of the nitrone, leading to high diastereofacial selectivity. The product exo-26b was obtained with 96-98% de. 

Frederickson, M. Optically Active Isoxazolidines via Asymmetric Cycloaddition Reactions of Nitrones with Alkenes-Applications in Organic Synthesis, Tetrahedron, 1997, 53, 403-425. 

Figure 16.14. IR map of an area (3x3 mm) of a KBr window in which resin beads of the isoxazolidine library are embedded. By application of the polystyrene absorption at 1942 cm 1 all resin beads were detected. White region KBr window gray region resin beads. There is a total of 297 resin beads in the scanned area.

Essentially all of the reactions of interest involve the opening of the five-membered ring. Reductive cleavages of the N—O bond in isoxazolines and isoxazolidines have been known for many years, and were reported on in the first edition. One recent application was the conversion of a fused isoxazoline (33) to a /1-amino ketone <88TL5917>. An alternative sequence leading to these synthetically useful compounds first quaternized the N of a perhydro compound (34) and then reacted the product with a tertiary amine <88TL5949>. If the quaternary salt (35) was reacted with lithium iodide, a readily separable mixture of the ketone (36) and (+ )-allosedamine (37) resulted (Scheme 9) <89CB2019>. 

Nitrones can undergo a variety of synthetically useful reactions 1,3-dipolar cycloaddition with alkenes and allqmes to isoxazolidines, nucleophilic addition which provide hydrojgrlamines, or Sm mediated cross couplings with carhonyl compounds affording vicinal amino alcohols.Recently, special attention is focused on the preparation and application of the optically pure cyclic nitrones, being used in the synthesis of biologically important molecules. ... 

An intramolecular application is illustrated in Scheme 20 (75,76) Pummerer reaction of the p-allyloxy-sulfoxides 83 produced the corresponding aldehydes 84, which were transformed one-pot into the transient nitrones 85. Under moderate heating, a fully regio- and diastereoselective intramolecular cycloaddition took place, leading to 6-fluoromethyl furo[3,4-c]isoxazolidines 86. Hydrogenolysis of the N-0 bond of 86 (R = Ph) provided the corresponding furo-amino alcohol 87. 

Nitrones are a readily available, stable class of 1,3-dipoles that can be utilized for stereoselective generation of isoxazolines and isoxazolidines. Spearheaded by Lebel s original reports in this area [42], countless applications of intramolecular nitrone [1, 3]-cycloadditions in complex target syntheses attest to the versatility of these transformations. Oppolzer disclosed a notable example in the synthesis of the alkaloid luciduline (4, Scheme 18.1) [43]. Heating of hydroxylamine 1 with para-formaldehyde furnished an intermediate nitrone 2 that participated in a highly regio- and stereoselective cycloaddition to give 3 in 87 % yield. 

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