1.3- Dipolar cycloaddition of cyclic nitrones

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). 

As part of an extensive study of the 1,3-dipolar cycloadditions of cyclic nitrones, Ali et al. (392-397) found that the reaction of the 1,4-oxazine 349 with various dipolarophiles afforded the expected isoxazolidinyloxazine adducts (Scheme 1.78) (398). In line with earlier results (399,400), oxidation of styrene-derived adduct 350 with m-CPBA facilitated N—O cleavage and further oxidation as above to afford a mixture of three compounds, an inseparable mixture of ketonitrone 351 and bicyclic hydroxylamine 352, along with aldonitrone 353 with a solvent-dependent ratio (401). These workers have prepared the analogous nitrones based on the 1,3-oxazine ring by oxidative cleavage of isoxazolidines to afford the hydroxylamine followed by a second oxidation with benzoquinone or Hg(ll) oxide (402-404). These dipoles, along with a more recently reported pyrazine nitrone (405), were aU used in successful cycloaddition reactions with alkenes. Elsewhere, the synthesis and cycloaddition reactions of related pyrazine-3-one nitrone 354 (406,407) or a benzoxazine-3-one dipolarophile 355 (408) have been reported. These workers have also reported the use of isoxazoles with an exocychc alkene in the preparation of spiro[isoxazolidine-5,4 -isoxazolines] (409). 

Perhydropyrrolo[l,2-fc]isoxazoles result from 1,3-dipolar cycloaddition of cyclic nitrones with alkenes. The high regio- and stereoselectivity of this cycloaddition has been used to control the stereochemistry in the synthesis of natural products. As one example, pyrroline N-oxide (70) and 3,4-dimethoxystyrene gave a diastereomeric mixture of pyrroloisoxazoles (71) and (72), in nearly quantitative yield with preferential formation of (71). 

Recent work has focused on developing catalytically controlled asymmetric 1,3-dipolar cycloadditions of cyclic nitrones such as 2,3,4,5-tetrahydropyridine IV-oxide 174. The Lewis acid iron complex 181 catalyzes the cycloaddition of 2,3,4,5-tetrahydropyridine jV-oxide 174 with methacrolein to give (3A,5A)-isoxazolidine 182 in good yield and high enantiomeric selectivity (Scheme 48) <2002JA4968>. The same catalyst 181 however gave (3R,4A,5R)-isoxazolidine 183 with much lower selectivity when crotonaldehyde was used. 

SCHEME 5.29 The exolendo selectivity in 1,3-dipolar cycloaddition of cyclic nitrones with olefins. 

The Jorgensen group reported the first highly diastereo- and enantioselective 1,3-dipolar cycloaddition of cyclic nitrones with alkenes catalysed by chiral 3,3 -aryl BINOL-AlMe complex 40, leading to optically active isoxazolidines in good yields, which were easily converted to optically active isoquinoline... 

The formation of enantiopure tricyclic compounds takes place by intramolecular 1,3-dipolar cycloadditions of acyclic nitrones to cyclic olefinic fragments (Scheme 2.214a,b) (706, 707a), or of cyclic nitrones to acyclic olefins (Scheme 2.214c) (116). Recently (707),b intramolecular nitrone cycloaddition reactions (according to Scheme 2.211a) have been applied in the synthesis of... 

The lower levels of stereocontrol which are often observed in the 1,3-dipolar cycloaddition of acyclic nitrones, as opposed to cyclic nitrones, could be accounted for by the possibility of interconversion of the nitrone geometry. One innovative solution to this problem is Aggarwal s recently reported 1,3-dipolar cycloadditions of the C2-symmetric cyclic alkenyl sulfoxide (l/ ,3/ )-2-methylene-1,4-dithiolane 1,3-dioxide (155) with acyclic nitrones.94 The presence of a C2 symmetry element in 155 means that the exo/endo approaches of 155 to a dipole are symmetry related and therefore identical, thereby reducing the number of possible transition states in the reaction. 1,3-Dipolar cycloaddition of 155 with nitrones 156a-c resulted in single diastereomeric 4,4-disubstituted isoxazolidine products (157a-c) (Scheme 42). Likewise 1,3-dipolar cycloadditions with other acyclic nitrones yielded single diastereomeric products. 

Synthesis of (5,5) systems via a (3 - - 2) approach is essentially based on 1,3-dipolar cycloaddition chemistry. Cyclic nitrones (e.g., (80)) react with phenyl isocyanates <74H(2)297, 76JA1478> and phenyl isothiocyanates <72TL4i9i, 73AJC2473> to form oxadiazolidines (81) by addition of the dipole exclusively to the C=N bond. However, with substituted phenyl isothiocyanates, dipolar cycloaddition... 

Dipolar cycloadditions of five-member cyclic nitrones to a,(3-unsaturated acid derivatives 99H(50)1213. 

In a more recent work the same research group has applied cyclic and acyclic vinyl ethers in the oxazaborolidinone-catalyzed 1,3-dipolar cycloaddition reaction with nitrones [30]. The reaction between nitrone 5 and 2,3-dihydrofuran 6 with 20 mol% of the phenyl glycine-derived catalyst 3c, gave the product 7 in 56% yield as the sole diastereomer, however, with a low ee of 38% (Scheme 6.9). 

We are the first group to succeed with the highly enantioselective 1,3-dipolar cycloadditions of nitronates [75]. Thus, the reaction of 5,6-dihydro-4H-l,2-oxazine N-oxide as a cyclic nitronate to 3-acryloyl-2-oxazilidinone, at -40 °C in dichloro-methane in the presence of MS 4 A and l ,J -DBFOX/Ph-Ni(II) complexes, gave a diastereomeric mixture of perhydroisoxazolo[2,3-fe][l,2]oxazines as the ring-fused isoxazolidines in high yields. The J ,J -DBFOX/Ph aqua complex prepared from... 

Dipolarophiles D3. 1,3-Dipolar cycloadditions of suitably functionalized cyclic nitrones with terminal alkenes, which have potential leaving groups X at the end of the alkane chain -(CHo),- (D3), were successfully used for the synthesis of pyrrolozidine, indolizidine and quinolizidine alkaloids, such as (+ )-and (—)-lentiginosine, a potent amyloglucosidase inhibitor (Scheme 2.243) (742). Reductive cleavage of the N-0 bond in the cycloadduct is important for the subsequent cyclization to pyrrolozidines, indolizidines, and quinolizidines. 

The reaction of 1,3-dipolar cycloaddition of enantiopure cyclic nitrones to protected allyl alcohol, is the basis of stereoselective syntheses of bicyclic N, O-iso-homonucleoside analogs (747), of isoxazolidine, to analogs of C-nucleosides related to pseudouridine (748) and to homocarbocyclic-2 -oxo-3 -azanucleosides (749) (Fig. 2.36). 

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). 

The retro-1,3-dipolar cycloaddition of imidazo[l,5- ][l,2,4]oxadiazoles 40, promoted by reaction with triphenylphos-phine at reflux in THF, gives the cyclic nitrones 187 (unreported yields) (Equation 15) <1997T13873>. The ring opening of compounds 40 leading to heterocycles 187 (Equation 15) can also be achieved thermally in the condensed phase under vacuum <1997TL2299>. 

The synthesis of 8-homocastanospermine via the 1,3-dipolar cycloaddition of five-membered cyclic nitrone derived from malic acid and unsaturated D-threo-hexaldonolactone is reported <2006CJC534>. 

The 1,3-dipolar cycloaddition of a five-membered cyclic nitrone derived from malic acid and unsaturated D-t/zreu-hexonolactone led to a single adduct 21, which was transformed into 1-homoaustraline via a sequence of well defined reactions (Fig. 7).16 Synthesis of similar derivatives was presented recently.17... 

The enantioselective catalytic 1,3-dipolar cycloaddition of linear or cyclic nitrones to enals was accomplished using the half-sandwich rhodium(III) complex S, Rc)-[(ri -C5Me5)Rh (/ )-Prophos (H20)](SbF6)2 as catalyst precursor [33, 34]. At —25°C, quantitative conversions to the cycloadducts, with up to 95% ee, were achieved (Scheme 10). The intermediate with the dipolarophile coordinated to the rhodium has been isolated and completely characterized, including the X-ray determination of its molecular structure [33, 34]. 

The power of cyclic chiral nitrones in synthesis was demonstrated by Nagasawa et al. (52) by the synthesis of the enantiomerically pure pentacyclic guanidine derivative 38 (Scheme 12.14). The 1,3-dipolar cycloaddition of 27b with 34 took... 

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