Isoxazolines, asymmetric

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... 

As discussed in Section 6.2, nitro compounds are good precursors of nitrile oxides, which are important dipoles in cycloadditions. The 1,3-dipolar cycloaddition of nitrile oxides with alkenes or alkynes provides a straightforward access to 2-isoxazolines or isoxazoles, respectively. A number of ring-cleaving procedures are applicable, such that various types of compounds may be obtained from the primary adducts (Scheme 8.18). There are many reports on synthetic applications of this reaction. The methods for generation of nitrile oxides and their reactions are discussed in Section 6.2. Recent synthetic applications and asymmetric synthesis using 1,3-dipolar cycloaddition of nitrile oxides are summarized in this section. 

An interesting antibody-catalyzed intermolecular asymmetric 1,3-dipolar cycloaddition reaction between 4-acetamidobenzonitrile N-oxide and N,N-dimethylacrylamide generating the corresponding 5-acylisoxazoline was observed (216). Reversed regioselectivity of nitrile oxide cycloaddition to a terminal alkene was reported in the reaction of 4-A rt-butylbenzonitrile oxide with 6A-acrylamido-6A-deoxy-p-cyclodextrin in aqueous solution, leading to the formation of the 4-substituted isoxazoline, in contrast to the predominance of the 5-substituted regioisomer from reactions of monosubstituted alkenes (217). 

Using a stoichiometric amount of (i ,i )-DIPT as the chiral auxiliary, optically active 2-isoxazolines can be obtained via asymmetric 1,3-dipolar addition of achiral allylic alcohols with nitrile oxides or nitrones bearing an electron-withdrawing group (Scheme 5-53).86a Furthermore, the catalytic 1,3-dipolar cycloaddition of nitrile oxide has been achieved by adding a small amount of 1,4-dioxane (Scheme 5-53, Eq. 3).86b The presence of ethereal compounds such as 1,4-dioxane is crucial for the reproducibly higher stereoselectivity. 

Under oxidation conditions, a C—C double bond can be functionalized by either two alkoxycarbonyl groups or one alkoxycarbonyl group and one heteroatom. As shown in Scheme 4.14, two ester groups are successfully introduced to styrene in an enantioselective manner, producing a phenylsuccinic ester using a Pd/MeO-BIPHEP complex. mcw-Diols are converted into cyclic ethers in an asymmetric manner when catalyzed by Pd/chiral bisoxazoline. Intramolecular aminopallada-tion followed by carbomethoxylation gives an cyclic amino ester in moderate ee when catalyzed by a Pd/bis(isoxazoline) complex. " ... 

From the 1980s on, many efforts were directed toward asymmetric induction of nitrile oxide cycloadditions to give pure (dia)stereoisomeric isoxazolines, and acyclic products derived from them (17,18,20-23). The need to obtain optically active cycloaddition products for use in the synthesis of natural products was first served by using chiral olefins, relying on 1,2-asymmetric induction, and then with optically active aldehydes or nitro compounds for the nitrile oxide part. In the latter case, insufficient induction occurs using chiral nitrile oxides, a problem still unsolved today. Finally, in the last 5 years, the first cases of successful asymmetric catalysis were found (29), which will certainly constitute a major area of study in the coming decade. 

Another approach that relies on asymmetric induction from the alkene part, uses chiral auxiliaries of various types, thereby leading to enantiomerically enriched or pure isoxazoline products. The complexity of some of these auxiliaries is high, and more economical solutions are desirable since the competition is the resolution of racemic cycloadducts with an overall efficiency up to 50% yield. With chiral nitrile oxides, the situation is much less satisfactory since asymmetric induction of the 1,4-type (with 1-alkenes) is minimal, and hardly better with a 1,3-relationship of inducing-forming stereocenters, when 1,2-disubstituted alkenes are employed (Scheme 6.22). Upon separation of the two diastereomers, however, another entry to pure optically active isoxazolines is available. 

Recently, the intramolecular nitrile oxide-alkene cycloaddition sequence was used to prepare spiro- w(isoxazolines), which are considered useful as chiral ligands for asymmetric synthesis (321). Reaction of the dibutenyl-dioxime (164) (derived from the diester 163) with sodium hypochlorite afforded a mixture of diastereomeric isoxazolines 165-167 in 74% combined yield (Scheme 6.80) (321). It was discovered that a catalytic amount of the Cu(II) complex 165-Cu(acac)2, where acac = acetylacetonate, significantly accelerated the reaction of diisopropylzinc... 

Yamamoto and co-workers (135,135-137) recently reported a new method for stereocontrol in nitrile oxide cycloadditions. Metal ion-catalyzed diastereoselective asymmetric reactions using chiral electron-deficient dipolarophiles have remained unreported except for reactions using a-methylene-p-hydroxy esters, which were described in Section 11.2.2.6. Although synthetically very useful and, hence, attractive as an entry to the asymmetric synthesis of 2-isoxazolines, the application of Lewis acid catalysis to nitrile oxide cycloadditions with Achiral 3-(2-alkenoyl)-2-oxazolidinones has been unsuccessful, even when > 1 equiv of Lewis acids are employed. However, as shown in the Scheme 11.37, diastereoselectivities in favor of the ft-cycloadducts are improved (diastereomer ratio = 96 4) when the reactions are performed in dichloromethane in the presence of 1 equiv of MgBr2 at higher than normal concentrations (0.25 vs 0.083 M) (140). The Lewis acid... 

Oppolzefs chiral auxiliary,6 (-)-2,10-camphorsultam, is useful in the asymmetric Diels-Alder reaction,3 4 and for the preparation of enantiomerically pure p-substituted carboxylic acids7 and diols,8 in the stereoselective synthesis of A2-isoxazolines,9 and in the preparation of N-fluoro (-)-2,10-camphorsultam, an enantioselective fluorinating reagent.10... 

A chiral zinc(II) complex derived from Et2Zn and diisopropyl (/ ,/ )-tartrate as a chiral auxiliary is applied to the asymmetric 1,3-dipolar cycloaddition of nitrile oxides to an achiral allylic alcohol, giving the corresponding (R)-2-isoxazolines with high enantioselectivity. Addition of a small amount of ethereal compounds such as DME and 1,4-dioxane is crucial for achieving the high asymmetric induction in a reproducible manner [71] (Eq. 8A.47). 

Reduction of isoxazolines, i-amino alcohols. Lithium aluminum hydride reduction of the ready available isoxazolines 1 is effected with unusually high 1,3-asymmetric induction (equation I). The stereoselectivity is not affected drastically by the presence of a hydroxyl group in the side chains at C3 or C5, but isoxazolines bearing a 4a-hydroxyl group are reduced almost entirely to the erythro ( fi)-diastereomer.1... 

Aspects of the stereoselectivity of nitrile oxide cycloaddition reactions have been reviewed (89G253). The most obvious stereochemical consequence of the cycloaddition is that the configuration of the alkene is retained in the product isoxazoline and this feature continues to be exploited in asymmetric synthesis. For example, the dehydrophenylalanine derivatives (42) gave the corresponding isoxazolines (43), stereospecifi-cally (Scheme 23) (91JHC1945). 

Dipolar cycloadditions between nitrones and alkenes to give isoxazolines are very important reactions in organic synthesis, because 1,3-amino alcohols can be synthesized from isoxazoline derivatives. Jprgensen and co-workers reported catalytic asymmetric... 

Aminopropanols (217, 218) can be prepared from alkenes and nitrile oxides via the LAH reduction of the isoxazoline intermediate 216." The stereospecificity of the reaction is surprisingly high. 1,3-Asymmetric induction leads to ratios of 1 19 for 217 and 218, respectively (R = Ph) and... 

Optically active sulfoxides of isoxazoline series in C—C asymmetric bond... 

Asymmetric 1,3-dipolar cycloaddition of nitrile oxides to allyl alcohol has been performed by Ukaji and coworkers [1542] in the presence of Et2Zn and (/V )-tartaric esters 2.69 in stoichiometric amounts at 0°C. Diisopropyl tartrate gjves the best results, and 2-isoxazolines are obtained with an excellent enantiose-lectivity (Figure 9.11). 

Arai et al. reported that asymmetric tandem cyclization of the dialkenyl alcohol 182 in the presence of Pd(II)— spiro bis(isoxazoline) catalyst gave the bicyclic heterocycle 183 in 89% yield with 82% ee (Scheme 61).132d The reaction proceeds through Wack-er-type oxypalladation, formation of the palladacycle 185 by carbopalladation of the resulting alkylpalla-dium intermediate 184, elimination of HX, and subsequent reductive elimination of Pd(0) to give the product 183. 

---