Allylic alcohols nitrile oxide cycloadditions

Several strategies have been proposed to improve the regioselectivity of nitrile oxide cycloaddition. Kanemasa and coworkers have reported high-rate acceleration and regioselectivity in nitrile oxide cycloadditions to the magnesium alkoxides of allylic and homoallylic alcohols (Eq. 8.64)."... 

Syntheses of Carbocyclic Compounds (1.V.2.V )-2 (.V )-Amino(4-metho-xyphenyl)methyl]cyclopropan-l-ol 392 (Scheme 1.45) has been prepared by a stepwise procedure involving a 1,3-dipolar nitrile oxide cycloaddition to allyl alcohol followed by a constmction of the cyclopropa d isoxazole system, and reduction of the bicycle (436). 

Since a magnesium alkoxide undergoes rapid ligand exchange with free alcohols even in dichloromethane at ambient temperature, the regiocontrol of nitrile oxide cycloadditions of multisubstituted allylic alcohols can be effectively attained... 

N/L recorded was 16,000 for the reactions using the magnesium aUcoxide of 3-methyl-2-buten-l-ol as a multisubstituted internal allylic alcohol substrate, which is why regiocontrol is still effective in the reactions in a highly coordinating solvent such as THE. Rate enhancement is much lower in the nitrile oxide cycloaddition reactions using homoallylic alcohol substrates. 

High stereo- and regiocontrol in nitrile oxide cycloadditions to allylic alcohols in the presence of magnesium ions (see Section 11.2.2) makes extension of this... 

On the other hand, the regioselectivity is not seriously affected by the choice of reaction solvent. Even when THF is used in the reaction with crotyl alcohol, the 2-isoxazoline-5-methanol regioisomer is the only product produced (Scheme 11.31). The reaction rate is decreased in THF, but is still much faster than that in the absence of magnesium ions. Kanemasa et al. (130) concluded that the magnesium-mediated nitrile oxide cycloadditions to allylic alcohols compete with the thermal... 

Nitrile oxides react with the methyl enol ethers of (Rs)-l -fluoro-alkyl-2-(p-tolylsulfinyl)ethanones to produce (45,5/f,/fs)-4,5-dihydroisoxazoles with high regio-and diastereo-selectivity.87 In the 1,3-dipolar cycloaddition of benzonitrile oxide with adamantane-2-thiones and 2-methyleneadamantanes, the favoured approach is syn, as predicted by the Cieplak s transition-state hyperconjugation model.88 The 1,3-dipolar cycloaddition reaction of acetonitrile oxide with bicyclo[2.2.l]hepta-2,5-diene yields two 1 1 adducts and four of six possible 2 1 adducts.89 Moderate catalytic efficiency, ligand acceleration effect, and concentration effect have been observed in the magnesium ion-mediated 1,3-dipolar cycloadditions of stable mesitonitrile oxide to allylic alcohols.90 The cycloaddition reactions of acryloyl derivatives of the Rebek imide benzoxazole with nitrile oxides are very stereoselective but show reaction rates and regioselectivities comparable to simple achiral models.91. 

The enantioselective total synthesis of the 13-membered macrolide fungal metabolite (+)-brefeldin A was accomplished using a triple chirality transfer process and intramolecular nitrile oxide cycloaddition in the laboratory of D. Kim. To set the correct stereochemistry at C9, the stereoselective ortho ester Claisen rearrangement was applied on a chiral allylic alcohol precursor. The rearrangement was catalyzed by phenol and it took place at 125 °C in triethyl orthoacetate to give 84% isolated yield of the desired diester. 

Natural polyketide macrolides cpothiloncs A and B were synthesized via a diastereoselective hydroxyl directed nitrile oxide cycloaddition and a new chemoselective protocol for isoxazoline reduction <01JOC6410, 01JA3611>. In particular, Mg(ll) directed 1,3-DC of nitrile oxides with chiral allylic alcohols 56 could be used to generate isoxazolines 57 in a high selective fashion <01AG(E)2082>, and conjugate A -isoxazolines, such as 58,... 

Houk KN, Moses SR, Wu Y-D, Rondan NG, Jager V, Schohe R, Fronczek FR (1984) Stereoselective nitrile oxide cycloadditions to chiral allyl ethers and alcohols. The inside alkoxy effect. J Am Chem Soc 106 3880-3882... 

Carreira has demonstrated that the hydroxy-directed nitrile oxide cycloaddition reaction is a general synthetic approach to polyketide fragments, with the intermediate isoxazolines functioning as latent, masked aldol adducts [65], The 1,3-dipolar cycloadditions have been shown to tolerate a large variety of alcohol substrates, including aliphatic allylic, homoallylic, and cyclic allylic alcohols [65-67], A demonstration of the versatility of the approach was reported in the synthesis of erythronolide A (58, Scheme 18.12) [67], This synthetic effort took advantage of two sequential hydroxy-directed nitrile oxide cycloadditions to provide fragments 55 and 57, both of which were obtained with excellent yields and diastereoselectivity (dr2 98 2). 

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-... 

The C(6)-C(15) segment was synthesized by Steps C-l and C-2. The stereoselectivity of the cycloaddition reaction between the nitrile oxide and allylic alcohol is the result of a chelated TS involving the Mg alkoxide.39... 

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... 

The application of microwaves to the cycloaddition reactions of allyl alcohols 180 with nitrile oxides not only achieved a substantial reduction of the reaction time and an improvement of the adduct yields, but also altered the regioselectivity of the cycloaddition in favor of the nonhydrogen bond-directed cycloadduct 182 (Scheme 9.55) [105]. 

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