Dipolar addition nitrone

A"-Octadienylatiori, rather than 0-octadienylation, of aldehyde oximes takes place to give the nitrone 37 as an intermediate, which undergoes 1.3-dipolar addition to butadiene, yielding the isoxazolidine 38[39],... 

A" -Isoxazolines, which are readily accessible by 1,3-dipolar addition of nitrones and nitronic esters to activated alkynes, undergo facile rearrangement upon warming (<110 °C)... 

Extensions of 1,3-dipolar additions of aromatic azides (720,721) to other enamines (636), and particularly to the enamine tautomer of SchilTs bases, were explored (722,723). Further nitrone additions were reported (724,725) and a double nitrile oxide added to an endiamine (647). Cyanogen azide and enamines gave cyanoamidines through rearrangement (726). 

Recently the synthetic method involving formation of the 1—5 and 3—4 bonds has been extended to the preparation of the completely hydrogenated system of A -substituted isoxazolidines (42). This interesting reaction results from 1,3-dipolar addition of nitrones (41) to olefins. " ... 

Diastereoselective intramolecular cycloaddition of nitrones is useful for constructing nitrogen- containing cyclic structures. The reaction serves as a key step in a number of natural product syntheses.63 Tufarriello and coworkers have used this strategy for preparing cocaine and other alkaloids.74 As a classical example, enantioselective total synthesis of (+)-luciduline is presented in Scheme 8.13, in which a useful feature of the 1,3-dipolar addition of nitrones is nicely illustrated.75... 

Dipolarophiles D15. Several examples employing N-alkyl- and /V-arylmalei-mides as dipolarophiles in the 1,3-dipolar addition to nitrones have been presented (257, 295b, 815, 816). 

Dipolar addition is closely related to the Diels-Alder reaction, but allows the formation of five-membered adducts, including cyclopentane derivatives. Like Diels-Alder reactions, 1,3-dipolar cycloaddition involves [4+2] concerted reaction of a 1,3-dipolar species (the An component and a dipolar In component). Very often, condensation of chiral acrylates with nitrile oxides or nitrones gives only modest diastereoselectivity.82 1,3-Dipolar cycloaddition between nitrones and alkenes is most useful and convenient for the preparation of iso-xazolidine derivatives, which can then be readily converted to 1,3-amino alcohol equivalents under mild conditions.83 The low selectivity of the 1,3-dipolar reaction can be overcome to some extent by introducing a chiral auxiliary to the substrate. As shown in Scheme 5-51, the reaction of 169 with acryloyl chloride connects the chiral sultam to the acrylic acid substrate, and subsequent cycloaddition yields product 170 with a diastereoselectivity of 90 10.84... 

Using a stoichiometric amount of (i ,i )-DIPT as the chiral auxiliary, optically active 2-isoxazolines can be obtained via asymmetric 1,3-dipolar addition of achiral allylic alcohols with nitrile oxides or nitrones bearing an electron-withdrawing group (Scheme 5-53).86a Furthermore, the catalytic 1,3-dipolar cycloaddition of nitrile oxide has been achieved by adding a small amount of 1,4-dioxane (Scheme 5-53, Eq. 3).86b The presence of ethereal compounds such as 1,4-dioxane is crucial for the reproducibly higher stereoselectivity. 

Yamamoto also applied N-triflyl phosphoramide 13b to the 1,3 dipolar addition of various electron-deficient diaryl nitrones and ethyl vinyl ether (Scheme 5.33)... 

The synthetic approach used in this work is shown in Scheme 9. Two known solution pathways were used to convert shikimic acid to an epoxide intermediate. In fact, both the (-)35 and the (+)36 enantiomers were formed. After minor synthetic transformations, these epoxides were linked to Ten-tagel S aminomethyl resin with an o-nitrophenyl-derived photocleavable linker 7437 via amide bond formation to give intermediate 75. The first point of variation was added via various iodo-benzyl nitrone carboxylic acids 76 via 1,3-dipolar addition/esterification reactions. Highly constrained resin-bound tetracyclic hydrooxazoles 77 were thereby produced. 

Intramolecular 1,3-dipolar additions of nitrones and nitrile oxides to carbohydrate alkene groups have met with success. Thus, treatment of the unsaturated heptose ether 68 (Scheme 17), which can be made following 1,3-dithianyl anion addition to C-l of 2,3,4-tri-0-benzyl-5,6-dideoxy-D-xy/o-hex-5-enose, with IV-methylhydroxylamine in refluxing methanol, affords the nitrone 69 that cyclizes to give the bicyclic isoxazolidine 70 (60% isolated) together with the epimer at the new asymmetric center carrying the methylene carbon atom (16% isolated) [35]. 

The completely reduced oxadiazole ring (26) was recently reported116 as an air oxidation product of a nitrimine. Presumably it was formed by a 1,3-dipolar addition of the intermediate nitrimine nitrone (25) to the nitrimine. The nitrimine results from the deoxygenation of a gem-nitrosonitro compound by triethyl phosphite [Eq. (31)]. 

With the complex [(indenyl)Ru(acetone)(Me4BIPHOP-F)]SbF6 as catalyst [22], the reaction afforded the exo cycloadduct as the major product for the reaction of acrolein with cyclopentadiene, whereas this noncatalyzed reaction is known to give the endo derivative as the major product. Analogously the catalyst 41 performed the asymmetric 1,3-dipolar addition of nitrones with enals [24]. 

Dipolar cycloadditions. Nitrones such as 1 combine with alkenes to form isoxazolidines. Tufariello has employed these 1,3-dipolar cycloadditionS as key steps in the synthesis of several alkaloids. Monosubstituted olefins react with nitrones regioselectively to afford 5-substituted iSoxazolidines thus addition of 2 to 1-pyrroline-l-oxide produces the cycioadduct 3, which serves as an intermediate in a total synthesis of elaeocarpine (4). ... 

The exolendo selectivity of the 1,3-dipolar addition of nitrones was regulated by the titanium salt as shown in Eq. (156) [398,399]. Aza-Cope rearrangement of a sugar-derived substrate initiated by the acetal cleavage with TiCl4 proceeded diastereoselec-tively to give the open-chain product (Eq. 157) [400]. 

Treatment of synlanti mixtures of aldoximes (69) with allylboronates generates N-(homoallyl)hydrox-ylamines (70) in good yield (Scheme 6). - The anti oxime reacts faster than the syn isomer. N-(Ho-moallyl)hydroxylamines (70) have been converted to homoallylamines (71) (with iron(II) dihydrolipoate) and have been treated with aldehydes to generate highly functionalized nitrone intermediates (72) for use in 1,3-dipolar addition reactions. 

The procedure described illustrates the use of 1,3-dipolar addition of nitrones to olefins for the preparation of isoxazoli-dines. The preparations of 2,3,5,5-tetraphenylisoxazolidine and ethyl 2,3-diphenyl-5-methylisoxazolidine-4-carboxylate, as described in Notes 9 and 10, respectively, indicate the versatility of the method. 

Klcmm has concluded that the 4-nitro derivative (55) results from electrophilic attack by NO on the unprotonated substrate. A mechanism involving 1,3-dipolar addition to the nitrone moiety and subsequent electrophilic attack is proposed to account for the formation of the 5-nitro isomer (54). 

Amikacin is more potent than kanamycin A and superior to BB-K19 (D,L-HABA) and BB-K31 (D(+)-HABA). Amikacin is the only important semisynthetic aminoglycoside on the market. In this connection two possibilities to synthesise the HABA moiety should be described. One of these syntheses starts with butyrolactone and uses the steps shown in Fig. 46 a. Another method utilizes the 1,3-dipolar addition of the nitrone ester 205 to ethyl acrylate (Fig. 46b). 

Dipolar addition of tricarbonylchromium-complexed nitrone 35 with electron-rich olefin was also achieved for the preparation of czs-3,5-disubstitut-ed isooxazolidine 36 much more stereoselectively than in the corresponding chromium uncomplexed arenas (Eq. 25) [22]. Also, an intramolecular version... 

Chiral nitrones were used in [3+2] qrcloadditions for the resolution of olefinic compounds. 1,3-Dipolar addition of an enantiomericaUy pure 3,4-dihydroxypyrrolidine-derived nitrone 61 onto racemic 2,3-dihydro-l-phenyl-IH-phosphole 1-oxide 62 led to a regio- and stereoselective formation of cycloadducts 63 and 64 combined with an efficient resolution of the phosphole oxide 62 [59]. The nitroxide 61a afforded a 66% yield of a 10 1 diastereomeric ratio for 63 64, the recovered phosphole 62 (21% yield, calculated on l.Sequiv phosphole initially involved) showing 59% ee. An increased (96%) ee for unreacted 62 was obtained from the reaction of 61b at higher conversion (91% yield of 63 64, calculated on nitrone). However, under these latter conditions, the yield of recovered (S)-62 was around 20% and the diastereoselectivity for 63 64 only 2.9 1. 

The nitrone 61b underwent stereoselective 1,3-dipolar addition to the sugar-derived racemic lactone 65, to give the adduct 66 (82% de). The unreacted 65 was recovered in 77% ee [60]. See Scheme 6.34 for a similar system used in an enantiodivergent reaction. 

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