Nitrile oxides cycloaddition

77d D-gl ucose, 77e D-mannose, catalysts used for ROMP Grubbs first- and second-generation ruthenium catalysts and Schrock catalyst Mo(CHCMe2Ph)(A/-2,6- PtjCgHjKO Buj.  

The attached isoxazoline moieties proved stable against hydrogenation of the polymer backbone via the tosylhydrazide route. A drawback is the separation of the endo and exo cycloadduct or the different reactivity of the isomers if a mixture is applied for polymerization. 

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Nitronates derived from primary nitroalkanes can be regarded as a synthetic equivalent of nitrile oxides since the elimination of an alcohol molecule from nitronates adds one higher oxidation level leading to nitrile oxides. This direct / -elimination of nitronates is known to be facilitated in the presence of a Lewis acid or a base catalyst [66, 72, 73]. On the other hand, cycloaddition reactions of nitronates to alkene dipolarophiles produce N-alkoxy-substituted isoxazolidines as cycloadducts. Under acid-catalyzed conditions, these isoxazolidines can be transformed into 2-isoxazolines through a ready / -elimination, and 2-isoxazolines correspond to the cycloadducts of nitrile oxide cycloadditions to alkenes [74]. 

By selection of conditions and catalyst, the intermediate hydroxyimine (11) can be directed to either (he hydroxy ketone (10) or amino alcohol (12), Over platinum oxide in methanol-acetic acid-water the amino alcohol forms, whereas over alkali-free Ra-Ni in methanol-water or over 10% Pd-on-C in methanol-water containing boric acid, the hydroxy ketones form in excellent yield. Nitrile oxide cycloadditions have been applied to five-membered ring syntheses (.50). 

Among the many recent applications to natural products, syntheses of pyrrolizidine and indolizidine alkaloids that take advantage of the 1,3-dipolar cycloaddition methodology have been reviewed [8]. The regio- and stereochemistry [9] as well as synthetic appHcations [10] of nitrile oxide cycloadditions have also been discussed. 

Although nitrile oxide cycloadditions have been extensively investigated, cycloadditions of silyl nitronates, synthetic equivalent of nitrile oxides in their reactions with olefins, have not received similar attention. Since we found that the initial cycloadducts, hl-silyloxyisoxazolidines, are formed with high degree of stereoselectivity and can be easily transformed into isoxazolines upon treatment with acid or TBAF, intramolecular silylnitronate-olefin cycloadditions (ISOC) have emerged as a superior alternative to their corresponding INOC reactions [43]. Furthermore, adaptability of ISOC reactions to one-pot tandem sequences involving 1,4-addition and ISOC as the key steps has recently been demonstrated [44]. 

Primary nitro ketones, ethyl nitroacetate, and (phenylsulfony l)nitromethane react with alkenes in the presence of Lewis acids to give nitrile oxide cycloaddition.61a Similarly, the reaction of a-nitro ketones with TeCl4 generates the corresponding nitrile oxides, as shown in Eq. 6.36.61b... 

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)."... 

Isoxazolines are good precursors of a,(3-unsaturated ketones.63,94 This transformation is useful for synthesis of polyenes. For example, nitrile oxide cycloaddition chemistry is used to prepare 4-oxo-2-alkenylphosphonates, which are useful to synthesize a long polyethylenic unit via Woodworth-Emmons olefination (Eq. 8.66).101... 

A potentially useful approach to the marine alkaloid papuamine based on INOC strategy is proposed as shown in Scheme 8.21. In fact, a tnms-hydrindane intermediate has been synthesized in racemic form using a model sequence of reactions involving a nitrile oxide cycloaddition as a key step (Eq. 8.69).106... 

Hassner and coworkers have developed a one-pot tandem consecutive 1,4-addition intramolecular cycloaddition strategy for the construction of five- and six-membered heterocycles and carbocycles. Because nitroalkenes are good Michael acceptors for carbon, sulfur, oxygen, and nitrogen nucleophiles (see Section 4.1 on the Michael reaction), subsequent intramolecular silyl nitronate cycloaddition (ISOC) or intramolecular nitrile oxide cycloaddition (INOC) provides one-pot synthesis of fused isoxazolines (Scheme 8.26). The ISOC route is generally better than INOC route regarding stereoselectivity and generality. 

Related to the nitrile oxide cycloadditions presented in Scheme 6.206 are 1,3-dipolar cycloaddition reactions of nitrones with alkenes leading to isoxazolidines. The group of Comes-Franchini has described cycloadditions of (Z)-a-phenyl-N-methylnitrone with allylic fluorides leading to enantiopure fluorine-containing isoxazolidines, and ultimately to amino polyols (Scheme 6.207) [374]. The reactions were carried out under solvent-free conditions in the presence of 5 mol% of either scandium(III) or indium(III) triflate. In the racemic series, an optimized 74% yield of an exo/endo mixture of cycloadducts was obtained within 15 min at 100 °C. In the case of the enantiopure allyl fluoride, a similar product distribution was achieved after 25 min at 100 °C. Reduction of the isoxazolidine cycloadducts with lithium aluminum hydride provided fluorinated enantiopure polyols of pharmaceutical interest possessing four stereocenters. 

It was found that 2-propenyloxymagnesium bromide reacts much more readily with nitrile oxides than other known dipolarophiles of electron-deficient, electron-rich, and strained types, including 3-buten-2-one, ethyl vinyl ether, and norbomene, respectively (147). Therefore, this BrMg-alkoxide is highly effective in various nitrile oxide cycloaddition reactions, including those of nitrile oxide/Lewis acid complexes. 

An unusual solvent effect was observed in cycloadditions of aromatic nitrile N-oxides with alkyl-substituted p-benzoquinones in ethanol-water (60 40) the reaction rates were 14-fold greater than those in chloroform (148). The use of ion pairs to control nitrile oxide cycloadditions was demonstrated. A chiral auxiliary bearing an ionic group and an associated counterion provides enhanced selectivity in the cycloaddition the intramolecular salt effect controls the orientation of the... 

Individual aspects of nitrile oxide cycloaddition reactions were the subjects of some reviews (161 — 164). These aspects are as follows preparation of 5-hetero-substituted 4-methylene-4,5-dihydroisoxazoles by nitrile oxide cycloadditions to properly chosen dipolarophiles and reactivity of these isoxazolines (161), 1,3-dipolar cycloaddition reactions of isothiazol-3(2//)-one 1,1-dioxides, 3-alkoxy- and 3-(dialkylamino)isothiazole 1,1-dioxides with nitrile oxides (162), preparation of 4,5-dihydroisoxazoles via cycloaddition reactions of nitrile oxides with alkenes and subsequent conversion to a, 3-unsaturated ketones (163), and [2 + 3] cycloaddition reactions of nitroalkenes with aromatic nitrile oxides (164). 

Cycloaddition with nitrile oxides occur with compounds of practically any type with a C=C bond alkenes and cycloalkenes, their functional derivatives, dienes and trienes with isolated, conjugated or cumulated double bonds, some aromatic compounds, unsaturated and aromatic heterocycles, and fullerenes. The content of this subsection is classified according to the mentioned types of dipolarophiles. Problems of relative reactivities of dienophiles and dipoles, regio- and stereoselectivity of nitrile oxide cycloadditions were considered in detail by Jaeger and... 

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). 

Isoxazolines 79, obtained from aromatic nitrile oxide cycloadditions to cyclohex-2-enone, reacted with nickel peroxide to give 3-aryl-6,7-dihydro[l] benzoisoxazol-4(5// )-ones 80. In contrast, the corresponding 2-bromocyclohex-2-enone underwent nitrile oxide cycloaddition, followed by dehydrobromination, to afford the regioisomeric 3-aryl-4,5-dihydro[l]benzoisoxazol-7(6//)-ones 81 (Scheme 1.23) (242). 

Cycloaddition of 5,6-dihydropyran-2-one with aromatic nitrile oxides leads to 3-aryl-3a,6,7,7a-tetrahydropyrano[3,4-d]isoxazol-4(47/)-ones 98. The latter react with nickel peroxide to give the corresponding dihydropyranoisoxazolones 99. Similar to 2-bromocyclohex-2-enone, 3-bromo-5,6-dihydropyran-2-one undergoes nitrile oxide cycloaddition, followed by dehydrobromination, to form regioi-someric 3-aryl-5,7-dihydropyrano 4,3-c/ isoxazol-7(4//)-ones 100 (Scheme 1.24) (242). 

Among heteroaromatic compounds able to react with nitrile oxides as dipo-larophiles, furan, probably, is the best known. Recently, a novel nitrile oxide was generated from a sulfoximine and converted in situ to a cycloadduct with furan (Scheme 1.25) (287). The starting racemic N-methyl-S-nitromethyl-S-phenylsul-foximine 124 was prepared in 87% yield via nitration of N,S-dimethyl-S-phenyl-sulfoximine. Reaction of 124 with p-chlorophenyl isocyanate and a catalytic quantity of triethylamine, in the presence of furan, afforded dihydrofuroisoxazole 125, the product of nitrile oxide cycloaddition, in 42% yield (65 35 diastereomer ratio). The reaction of 125 with phenyllithium and methyllithium afforded compounds 126, which are products formed by replacement of the sulfoximine group by Ph and Me, respectively. 

Intramolecular Cycloaddition Intramolecular nitrile oxide cycloaddition (INOC) is widely used in the synthesis of various compounds, particularly, natural products. This field is reviewed in detail in Chapter 6 of the mono-graph/Reference 5 and also in Reference 400 limited to nitrile oxides generated from nitroalkenes. Some features of INOC are illustrated in this subsection by new data and those omitted in Reference 5. 

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). 

A synthetic approach to hyperevolutin A 421, prenylated bicyclo[3.3.1] nonanone derivative, with an acylated phloroglucinol-type fragment, has been described (464). Intramolecular allene-nitrile oxide cycloaddition of 422 has been used to construct the bicyclic framework and the vicinal quaternary centers in cycloadduct 423. 

An expedient and fully stereocontrolled synthesis of epothilones A (435, R = H) and B (435, R = Me) has been realized (473, 474). The routes described, involve an extensive study of nitrile oxide cycloadditions, as substitutes for aldol addition reactions, leading to the realization of a highly convergent synthesis, based on the Kanemasa hydroxyl-directed nitrile oxide cycloaddition. 

Two stereoselective aldol reactions, followed by a nitrile oxide cycloaddition and a stereoselective late-stage epoxidation are the key steps in the total synthesis of myriaporones 1, 3, and 4 (436, 437, and 438). The synthesis allows... 

Three novel stereo- and regioselective schemes for the total synthesis of (+ )-brefeldin A 440 have been accomplished. Each of them exploit intermolec-ular nitrile oxide cycloaddition for constructing the open chain and introducing substituents, but differ in subsequent stages. The first (480) and the second (481) use intramolecular cycloaddition for the macrocycle closure. However, in the second scheme INOC is followed by C=C bond cis-trans-isomerization. In the third scheme (481) intermolecular cycloaddition is followed by ring closing metathesis as the key step. 

The synthesis of the spiroisoxazoline natural product (+ )-calafianin 447 has been reported, using asymmetric nucleophilic epoxidation and nitrile oxide cycloaddition as key steps. Syntheses and spectral analyses of all calafianin stereoisomers lead to unambiguous assignments of relative and absolute stereochemistry (494). 

R = h, Me, Ph. INOC intramolecular nitrile oxide cycloaddition. Scheme 3.140... 

Intramolecular nitrile oxide cycloaddition. The conjugate addition of t-butyl isocyanide to a nitroalkene can generate a nitrile oxide, which can be trapped intramolecularly by a double bond to form an isoxazoline. 

Intramolecular [3+2] dipolar cycloadditions have also been employed as a post-Ugi transformation to generate heterobicyclic structures, namely fused isoxazolines [130], isoxazoles [130] and triazoles [131] (Fig. 31). Isoxazoles were obtained through intramolecular nitrile oxide cycloaddition. The precursor of the nitrile oxide (a nitro group) was introduced into the carboxylic component, while a triple bond was positioned in the starting amine. Treatment of 152 with POCl3/Et3N gave the intermediate nitrile oxide, which spontaneously cyclized to isoxazoles 153. 

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