Isoxazolidines nitrone-alkene

The intramolecular nitrone-alkene cycloaddition (INAC) of hept-6-enoses 110 can proceed either via the exo-mode to give fused isoxazolidines 111 or the endo-mode to give the bridged 1,2-oxazocines 112 (Scheme 23). 

Intramolecular nitrone-alkene cycloaddition. Reaction of cycloalkanones substituted by a 3-(2-propenyl) or a 3-(3-butenyl) side chain with alkylhydroxylamines with azeotropic removal of water results in a bridged bicycloalkane fused to an isoxazolidine ring. The transformation involves formation of a nitrone that undergoes intramolecular cycloaddition with the unsaturated side chain. 

The reaction of various organometallic reagents with the ketone (21) leading to the branched-chain sugars (22) has been described (Scheme 6)." The products were used to prepare cyclopentane fused isoxazolidines (23) by a nitrone-alkene cycloaddition process (see Clhapter 18). 

Isoxazolidines sometimes undergo retro 1,3-dipolar cycloaddition to give back alkenes and nitrones (77AHC(2D207). 

The preparation of isoxazolidine derivatives was first reported by Bodforss in 1918 (18CB192). The major synthesis of isoxazolidines involves the cycloaddition of nitrones with alkenes, and isoxazolidines have also enjoyed an increasing use as key intermediates in the synthesis of natural products and other heterocycles (79ACR396, 1892CB1498, 1892CB3291, 1882CB2105). 

Nitrones or aci-nitro esters react with alkenes to give in some cases A/-substituted isoxazolidines and in others 2-isoxazolines. When the intermediate isoxazolidines were observed, a number of procedures transformed them into the 2-isoxazolines. Acrylonitrile and phenyl rzcf-nitrone esters produced an A/-methoxyisoxazolidine. Treatment with acid generated a 2-isoxazole while treatment with base generated an oxazine (Scheme 118) (68ZOR236). When an ethoxycarbonyl nitrone ester was reacted with alkenes, no intermediate isoxazolidine was observed, only A -isoxazolines. Other aci-mtro methyl esters used are shown in Scheme 118 and these generate IV-methoxyisoxazolidines or A -isoxazolines which can be further transformed (72MI41605). 

Chiral nitrones react with alkenes to produce 3,5-disubstituted isoxazolidines that are nonracemic diastereomeric mixtures and are oriented predominantly cis (equation 53) (77CC303, 79JOC1212). 

A newer method for the preparation of nitronic esters, namely utilizing the (9-trimethyl-silyl ester, has been reported and these are prepared by the reaction of alkylnitro compounds and (V,(V-bis(trimethylsilyl)acetamide. These nitronic esters also undergo cycloaddition with alkenes to produce isoxazolidines (equation 54) (74MIP41601, 74DOK109, 78ACS(B)ll8). 

Steroidal alkene (531a) reacted with a nitronic ester at 14 000 atmospheres to produce an isoxazolidine (532a) (80IZV1893). 

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]. 

The 1,3-dipolar cycloaddition reaction of nitrones with alkenes gives isoxazolidines is a fundamental reaction in organic chemistry and the available literature on this topic of organic chemistry is vast. In this reaction until three contiguous asymmetric centers can be formed in the isoxazolidine 17 as outlined for the reaction between a nitrone and an 1,2-disubstituted alkene. The relative stereochemistry at C-4 and C-5 is always controlled by the geometric relationship of the substituents on the alkene (Scheme 8.6). 

Nitrones, reactive 1,3-dipoles, react with alkenes and alkynes to form isoxazolidines and isoxazolines, respectively. With monosubstituted olefinic dipolarophiles, 5-substituted isoxazolidines are generally formed predominantly however, with olefins bearing strongly electron-withdrawing groups, 4-substituted derivatives may also be formed.631... 

The mechanism of 1,3-dipolar cycloaddition can be found in Ref. 63 and the references within. The reaction of nitrone with 1,2-disubstituted alkenes creates three contiguous asymmetric centers, in which the geometric relationship of the substituents of alkenes is retained. The synthetic utility of nitrone adducts is mainly due to their conversion into various important compounds. For instance, P-amino alcohols can be obtained from isoxazolidines by reduction with H2-Pd or Raney Ni with retention of configuration at the chiral center (Eq. 8.44). 

Cycloaddition of the cyclic nitrone derived from proline benzyl ester with alkenes proceeds readily to give isoxazolidines with good regio-and stereoselectivity (Eq. 8.47).68 The reaction favors exo-mode addition. However, certain cycloadditions are reversible and therefore the product distribution may reflect thermodynamic rather than kinetic control. 

Asymmetric 1,3-dipolar cycloaddition of cyclic nitrones to crotonic acid derivatives bearing chiral auxiliaries in the presence of zinc iodide gives bicyclic isoxazolidines with high stereoselectivity (Eq. 8.51). The products are good precursors of (3-amino acids such as (+)sedridine.73 Many papers concerning 1,3-dipolar cycloaddition of nitrones to chiral alkenes have been reported, and they are well documented (see Ref. 63). 

Catalytic enantioselective 1,3-dipolar cycloaddition between nitrones with alkenes using a novel heterochiral ytterbium(III) catalyst is reported (Eq. 8.58).91 The desired isoxazolidine derivatives are obtained in excellent yields with excellent diastereo- and enantioselectivities. 

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. 

Cycloaddition of N-substituted C -phosphorylated nitrones (496) to terminal alkenes leads to C-5 substituted isoxazolidines (497) and (498) with moderate (20%) to high (up to 90%) trans to cis diastereoselectivities (Scheme 2.241) (Table 2.20). In ZnCl2-catalyzed cycloadditions, mixtures enriched in cis diastere-omers were produced (263). 

Cycloadditions of cyclic (a) and acyclic (b) nitrones to achiral (535a) and chiral a-diphenylphosphinyl alkenes (535b,c) have been reported (752). In each case, addition to allyldiphenylphosphine oxide (535a) gave a single isoxazolidine... 

The influence of electronic factors on the regioselective cycloadditions of nitrones (551), and (583) to (585) to acrylates has been demonstrated by using dipolarophiles with electrophilic substituents at the P-carbon of the alkene in y-bromo a, 3-unsaturated esters and lactones (774) and in ethyl 2-hydroperfluoro-2-alkenoates (586) (775). The reactions of enoates (586) with nitrones are regio-specific and afford isoxazolidines with the CC>2Et and R/, groups in C-4 and C-5... 

The 1,3-dipolar cycloaddition of nitrones to vinyl ethers is accelerated by Ti(IV) species. The efficiency of the catalyst depends on its complexation capacity. The use of Ti( PrO)2Cl2 favors the formation of trans cycloadducts, presumably, via an endo bidentate complex, in which the metal atom is simultaneously coordinated to the vinyl ether and to the cyclic nitrone or to the Z-isomer of the acyclic nitrones (800a). Highly diastereo- and enantioselective 1,3-dipolar cycloaddition reactions of nitrones with alkenes, catalyzed by chiral polybi-naphtyl Lewis acids, have been developed. Isoxazolidines with up to 99% ee were obtained. The chiral polymer ligand influences the stereoselectivity to the same extent as its monomeric version, but has the advantage of easy recovery and reuse (800b). 

Cycloaddition of 3-methylenephthalide with ot./V-diphenylnitrone gave two diastereoisomers of 2,3-diphenyl-2,3-dihydrospiro 1,3-oxazole-5(47/ )l (3 H)-2-benzoluran]-3 -one (805). The 1,3-dipolar cycloaddition reaction of /V-benzyl-C-(2-furyl)nitrones with electron-rich alkenes gave preferentially trans-3,5-disubstituted isoxazolidines (endo approach). These experimental results are in good qualitative agreement with those predicted from semiempirical (AMI and PM3) and ab initio (HF/3-21G) calculations (806). 

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