Nitrile oxides asymmetric reactions

The first, and so far only, metal-catalyzed asymmetric 1,3-dipolar cycloaddition reaction of nitrile oxides with alkenes was reported by Ukaji et al. [76, 77]. Upon treatment of allyl alcohol 45 with diethylzinc and (l ,J )-diisopropyltartrate, followed by the addition of diethylzinc and substituted hydroximoyl chlorides 46, the isoxazolidines 47 are formed with impressive enantioselectivities of up to 96% ee (Scheme 6.33) [76]. 

Zinc-tartrate complexes were applied for reactions of both nitrones and nitrile oxides with allyl alcohol and for both reaction types selectivities of more than 90% ee were obtained. Whereas the reactions of nitrones required a stoichiometric amount of the catalyst the nitrile oxide reactions could be performed in the presence of 20 mol% of the catalyst. This is the only example on a metal-catalyzed asymmetric 1,3-dipolar cycloaddition of nitrile oxides. It should however be no-... 

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. 

It has recently been found that Et2Zn promotes the 1,3-dipolar cycloaddition of nitrile oxides to allyl alcohol in the presence of catalytic amounts of diisopropyl tartrate (DIPT). By this method, 2-isoxazlines are obtained in good yields and up to 96% ee (Eq. 8.73).124a A positive nonlinear effect (amplification of ee of the product) has been observed in this reaction. There is an excellent review on positive and negative nonlinear effects in asymmetric induction.124b... 

Dipolar cycloaddition reactions are of main interest in nitrile oxide chemistry. Recently, reviews and chapters in monographs appeared, which are devoted to individual aspects of these reactions. First of all, problems of asymmetric reactions of nitrile oxides (130, 131), including particular aspects, such as asymmetric metal-catalyzed 1,3-dipolar cycloaddition reactions (132, 133), development of new asymmetric reactions utilizing tartaric acid esters as chiral auxiliaries (134), and stereoselective intramolecular 1,3-dipolar cycloadditions (135) should be mentioned. Other problems considered are polymer-supported 1,3-dipolar cycloaddition reactions, important, in particular, for combinatorial chemistry... 

However, most asymmetric 1,3-dipolar cycloaddition reactions of nitrile oxides with alkenes are carried out without Lewis acids as catalysts using either chiral alkenes or chiral auxiliary compounds (with achiral alkenes). Diverse chiral alkenes are in use, such as camphor-derived chiral N-acryloylhydrazide (195), C2-symmetric l,3-diacryloyl-2,2-dimethyl-4,5-diphenylimidazolidine, chiral 3-acryloyl-2,2-dimethyl-4-phenyloxazolidine (196, 197), sugar-based ethenyl ethers (198), acrylic esters (199, 200), C-bonded vinyl-substituted sugar (201), chirally modified vinylboronic ester derived from D-( + )-mannitol (202), (l/ )-menthyl vinyl ether (203), chiral derivatives of vinylacetic acid (204), ( )-l-ethoxy-3-fluoroalkyl-3-hydroxy-4-(4-methylphenylsulfinyl)but-1 -enes (205), enantiopure Y-oxygenated-a,P-unsaturated phenyl sulfones (206), chiral (a-oxyallyl)silanes (207), and (S )-but-3-ene-1,2-diol derivatives (208). As a chiral auxiliary, diisopropyl (i ,i )-tartrate (209, 210) has been very popular. 

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). 

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. 

Substituted 4,5-dihydro-5-vinylisoxazoles (40), obtained by regio- and stereospecific cycloaddition of nitrile oxides to dienes, undergo smooth osmium-catalyzed c/s-hydro-xylation to give amino-polyol precursors (equation 28)45. The reaction is anti selective, the diastereomeric ratios ranging from 73 27 up to 99 1. Highest stereoselectivities were observed when R3 was methyl. Thus, whereas osmylation of 40a afforded a 78 22 mixture of 41a and 42a, respectively, in 80% overall yield, similar treatment of 40b resulted in a 92 8 mixture of 41b and 42b, respectively, in 70% overall yield. The cycloaddition-osmylation sequence allows control of the relative configuration of up to 4 contiguous asymmetric centers. 

The [2 + 3] cycloaddition reaction of nitrile oxides, easily accessible from corresponding aldoximes, with different alkenes is known as an excellent route to isoxazohne derivatives . The reactions of asymmetric addition ° or addition of unsaturated ger-manes and stannanes to nitrile oxides were reviewed in recent years. In this subsection only the main directions of the synthesis of isoxazole derivatives are briefly reported. 

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-isoxazohnes, the application of Lewis acid catalysis to nitrile oxide cycloadditions with 4-chiral 3-(2-aIkenoyl)-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 ffc-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... 

Many groups have tackled the development of catalytic asymmetric versions of nitrile oxide cycloaddition reactions using chiral Lewis acid catalysts. However, Ukaji is the first and the only chemist who has succeeded in the achievement of such processes involving nitrile oxide cycloaddition reactions. He studied reactions... 

The first antibody-catalyzed asymmetric 1,3-dipolar cycloaddition was reported recently by Janda and co-workers (382). The reaction of the relatively stable nitrile oxide 280 and dimethyl acrylamide 281 was catalyzed by antibody 29G12 having turnover numbers >50, and the product 282 was obtained in up to >98% ee (Scheme 12.89). The antibody 29G12 was formed for hapten 283 and coupled to a carrier protein by standard protocols. The hapten 283 contains no chiral center and therefore the immune system elicited a stereochemical environment capable of stabilizing the enantiomeric transition state leading to 282. 

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