Acrylamides, nitrile oxide cycloadditions

The 1,3-dipolar cycloaddition of a variety of aromatic and aliphatic nitrile oxides to 2.5-/ra//.v-2.5-diphenylpyrrolidine-derived acrylamide and cinnamamide 399, efficiently affords the corresponding 4,5-dihydroisoxazole-5-carboxamides 400 in highly regio- and stereoselectivity (Scheme 1.47). Acid hydrolysis of these products affords enantiopure 4,5-dihydroisoxazole-5-carboxylic acids 401 (443). 

When acrylamides are used as dipolarophUes, FMO theory predicts that the 4-amido isomer should be preferred, which is contrary to the results found with tertiary amides (129). Semiempirical, ab initio, and density functional theory (DFT) calculations were applied to the regioisomeric transition state stmctures of benzonitrile oxide cycloadditions (129-131). The results suggest that there is an unfavorable steric repulsion between the phenyl ring of the nitrile oxide and the methyl group of the ester (or amide) functionalities of the dipolarophile in the transition state leading to the 4-acyl regioisomer (Scheme 6.17). 

The use of chiral auxiliaries to induce (or even control) diastereoselectivity in the cycloaddition of nitrile oxides with achiral alkenes to give 5-substituted isoxazolines has been investigated by a number of groups. With chiral acrylates, this led mostly to low or modest diastereoselectivity, which was explained in terms of the conformational flexibility of the vinyl-CO linkage of the ester (Scheme 6.33) (179). In cycloadditions to chiral acrylates (or acrylamides), both the direction of the facial attack of the dipole as well as the conformational preference of the rotamers need to be controlled in order to achieve high diastereoselection. Although the attack from one sector of space may well be directed or hindered by the chiral auxiliary, a low diastereomer ratio would result due to competing attack to the respective 7i-faces of both the s-cis and s-trans rotamers of the acrylate or amide. 

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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