Nitrones acyclic chiral

More recently, Bravo et al. [158] described the synthesis of optically pure fluoro-substituted isoxazolidines by 1,3-dipolar cycloaddition of acyclic nitrones to chiral methyl enol ethers of 3-fluoro-l-sulfinyl-2-propanones. Reaction of 191b with 200 (room temperature, 10 days) afforded only one adduct, exo(t)-... 

Few examples of nitrone cycloadditions to acyclic chiral alkenes have been reported84-89. (More recent literature can be found ill references 322 -336.) A-Benzylnitrones add in a poorly stereoselective fashion to benzyl (,S )-1 -metho.xycarbonyl-2-propenylcarbarnate to give (5RIS)-2-benzyl-5-[(benzyloxycarbonyl)methoxycarbonylmethyl]isoxazolidine as precursors of /1-hydroxy ornithinesss. 

The above described reaction has been extended to the application of the AlMe-BINOL catalyst to reactions of acyclic nitrones. A series chiral AlMe-3,3 -diaryl-BINOL complexes llb-f was investigated as catalysts for the 1,3-dipolar cycloaddition reaction between the cyclic nitrone 14a and ethyl vinyl ether 8a [34], Surprisingly, these catalysts were not sufficiently selective for the reactions of cyclic nitrones with ethyl vinyl ether. Use of the tetramethoxy-substituted derivative llg as the catalyst for the reaction significantly improved the results (Scheme 6.14). In the presence of 10 mol% llg the reaction proceeded in a mixture of CH2CI2 and petroleum ether to give the product 15a in 79% isolated yield. The diastereoselectiv-ity was the same as in the acyclic case giving an excellent ratio of exo-15a and endo-15a of >95 <5, and exo-15a was obtained with up to 82% ee. 

N-donor ligand. The reaction appears to proceed via an acyclic iminoplatinum(II) intermediate that undergoes a subsequent intramolecular cyclization. Some mechanistic aspects of this versatile reaction have been elucidated.225,226 A4-l,2,4-oxadiazolines have been prepared by the [2+3] cycloaddition of various nitrones to coordinated benzonitrile in m-[PtCl2( D M SO)(PhCN)] precursors.227,228 Racemic and chiral [PtCl2(PhMeSO)(PhCN)] complexes have also been used in order to introduce a degree of stereoselectivity into the reaction, resulting in the first enantioselective synthesis of A4-l,2,4-oxadiazolines, which can be liberated from the complexes by the addition of excess ethane-1,2-diamine. 

Various kinds of chiral acyclic nitrones have been devised, and they have been used extensively in 1,3-dipolar cycloaddition reactions, which are documented in recent reviews.63 Typical chiral acyclic nitrones that have been used in asymmetric cycloadditions are illustrated in Scheme 8.15. Several recent applications of these chiral nitrones to organic synthesis are presented here. For example, the addition of the sodium enolate of methyl acetate to IV-benzyl nitrone derived from D-glyceraldehyde affords the 3-substituted isoxazolin-5-one with a high syn selectivity. Further elaboration leads to the preparation of the isoxazolidine nucleoside analog in enantiomerically pure form (Eq. 8.52).78... 

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 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). 

Cyclic chiral nitrones generally offer better stereoselectivity than their acyclic counterparts. A more efficient shielding of one of the nitrone faces is often obtained due to the more rigid conformation of the cyclic nitrones. Furthermore, in this approach, ( /Z)-interconversion is avoided and cyclic nitrones are often more reactive since they, depending on the substitution pattern, are usually locked in the... 

Saito et al. (32,121) developed a variety of tartaric acid derivatives, including Ci-symmetric chiral alkenes such as 76. The 1,3-dipolar cycloaddition between 76 and 77 gave primarily endo-1%. (Scheme 12.26) The diastereofacial selectivity of the reaction is excellent, as endo-1% is obtained with >98% de. Other cyclic and acyclic nitrones have been employed in reactions with 76, and in all cases, moderate to excellent endo/exo-selectivities and excellent diastereofacial selectiv-ities were obtained (32,121). Three other research groups have applied various y-hydroxylated ot,p-unsaturated carbonyl compounds in related reactions with nitrones (122-124). However, the selectivities were somewhat lower than those obtained by Saito and et al. (32,121). 

Chiral exocyclic alkenes such as 112, also having the chiral center two bonds away from the reacting alkene moiety, have been used in highly diastereoselective reactions with azomethine ylides, and have been used as the key reaction for the asymmetric synthesis of (5)-(—)-cucurbitine (Scheme 12.37) (169). The aryl sulfone 113 was used in a 1,3-dipolar cycloaddition reaction with acyclic nitrones. In 113, the chiral center is located four bonds apart from alkene, and as a result, only moderate diastereoselectivities of 36-56% de were obtained in these reactions (170). 

The amino acid derived chiral oxazolidinone 188 is a very commonly used auxiliary in Diels-Alder and aldol reactions. However, its use in diastereoselective 1,3-dipolar cycloadditions is less widespread. It has, however, been used with nitrile oxides, nitrones, and azomethine ylides. In reactions of 188 (R = Bn, R =Me, R = Me) with nitrile oxides, up to 92% de have been obtained when the reaction was performed in the presence of 1 equiv of MgBr2 (303). In the absence of a metal salt, much lower selectivities were obtained. The same observation was made for reactions of 188 (R = Bn, R = H, R = Me) with cyclic nitrones in an early study by Murahashi et al. (277). In the presence of Znl2, endo/exo selectivity of 89 11 and up to 92% de was observed, whereas in the absence of additives, low selectivities resulted. In more recent studies, it has been shown for 188 (R =/-Pr, R = H, R =Me) that, in the presence of catalytic amounts of Mgl2-phenanthroline (10%) (16) or Yb(OTf)3(20%) (304), the reaction with acyclic nitrones proceeded with high yields and stereoselectivity. Once again, the presence of the metal salt was crucial for the reaction no reaction was observed in their absence. Various derivatives of 188 were used in reactions with an unsubstituted azomethine ylide (305). This reaction proceeded in the absence of metal salts with up to 60% de. The presence of metal salts led to decomposition of the azomethine ylide. 

Chiral crotonates derived from S-citroncllol, l-(—)-menthol, and S-solketol undergo 1,3-dipolar cycloaddition with cyclic and acyclic nitrones.66 Asymmetric 1,3-dipolar cycloaddition of optically active hifluoromethylated a, /l-unsaturated aiyl sulfones (43) with nitrones yield the corresponding isoxazolidmes (44) and (45) with high regio- and... 

The products are generated in good to excellent yields and with a high level of chiral induction. The reaction can be applied to cyclic and acyclic nitrones whereas only (X, 3-unsaturated aldehydes are applicable as the dipolarophile. 

The observed high anti selectivity may reflect the acyclic extended transition-state mechanism postulated in the fluoride-catalyzed reactions (Figure 9.1) [27]. Judging from the product configuration, chiral ammonium cation should effectively cover the si- face of the nitronate and the selective approach of aldehyde from the re-face should result. 

Nitrones were the first as well as the most widely used dipoles in asymmetric cycloadditions. The first report on the use of enantiomerically pure vinylsulf-oxides as dipolarophiles was due to Koizumi et al. [153], who described in 1982 the reaction of (-R)-vinyl p-tolyl sulfoxide 1 with acyclic nitrones 191. The reactions required 20 h in refluxing benzene to be completed, yielding a mixture of only two compounds, 192 and 193 (Scheme 91). They exhibited identical endo or exo stereochemistry (which was not unequivocally assigned), deduced from the fact that their reduction yielded enantiomeric thioethers. The major component, 192, exhibits (S) configuration at C-3, determined by chemical correlation. The authors claim this paper [153] to be the first example of 1,3-dipolar cycloaddition using chiral dipolarophiles. 

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