Nitrones, catalytic asymmetric 1,3-dipolar

Since then, optically active a-aminophosphonates have been obtained by a variety of methods including resolution, asymmetric phosphite additions to imine double bonds and sugar-based nitrones, condensation of optically active ureas with phosphites and aldehydes, catalytic asymmetric hydrogenation, and 1,3-dipolar cycloadditions. These approaches have been discussed in a comprehensive review by Dhawan and Redmore.9 More recent protocols involve electrophilic amination of homochiral dioxane acetals,10 alkylation of homochiral imines derived from pinanone11 and ketopinic acid,12 and alkylation of homochiral, bicyclic phosphonamides.13... 

Taking advantage of the Lewis acidic character of the cationic ruthenium complex 107, catalytic asymmetric 1,3-dipolar cycloadditions of nitrones have been developed [113]. In the presence of 5 mol % of 107, the cycloaddition of 108 with crotonaldehyde afforded an isoxazolidine 109 in 80% yield with 66% ee (Eq. 47). 

Catalytic asymmetric 1,3-dipolar cycloaddition of a nitrone with a dipolarophile has been performed using a chiral scandium catalyst [31]. The chiral catalyst, which was effective in asymmetric Diels-Alder reactions, was readily prepared from Sc(OTf)3, (7 )-(-i-)-BINOL, and d5 -l,2,6-trimethylpiperidine. The reaction of benzylbenzylide-neamine A-oxide with 3-(2-butenoyl)-l,3-oxazolidin-2-one was performed in the presence of the chiral catalyst to yield the desired isoxazolidine in 69 % ee with perfect diastereoselectivity (endolexo = > 99 1) (Sch. 8) [31,46], It was found that reverse enantioselectivity was observed when a chiral Yb catalyst, prepared from Yb(OTf)3, the same (i )-(-i-)-BINOL, and cd-l,2,6-trimethylpiperidine, was used instead of the Sc catalyst under the same reaction conditions. 

Dipolar cycloadditions between nitrones and alkenes to give isoxazolines are very important reactions in organic synthesis, because 1,3-amino alcohols can be synthesized from isoxazoline derivatives. Jprgensen and co-workers reported catalytic asymmetric... 

The greater part of this chapter is concerned with the Diels-Alder and hetero-Diels-Alder reaction. The asymmetric version of both of these reactions can be catalysed with metal-based Lewis acids and also organocatalysts. The catalytic asymmetric 1,3-dipolar cycloaddition of nitrones and azomethine ylides is also discussed. Again, most success in this area has been achieved using metal-based Lewis acids and the use of organocatalysts is begiiming to be explored. This chapter concludes with a brief account of recent research into the asymmetric [2+2]-cycloaddition, catalysed by enantiomerically pure Lewis acids and amine bases, and also the Pauson-Khand [2- -2- -l] cycloaddition mediated by titanium, rhodium and iridium complexes. 

Very recently, Maruoka reported an alternative catalytic asymmetric [3 + 2] cycloaddition reaction between various nitrones and acrolein catalyzed by the x-oxo-type chiral bis-Ti(IV) oxide, giving rise to the corresponding isoxazolidine derivatives in good yields and high enantioselectivities [177]. This type of titanium Lewis acid has also been used in enantioselective 1,3-dipolar cycloaddition of diazoacetates to various substituted acroleins, affording 2-pyrazolines with a chiral quarternary carbon center (Scheme 14.78) [178]. The products obtained with these methodologies have been applied to the synthesis of natural product and biologically important molecules. 

Several successful chiral catalysts have been reported so far for catalytic asymmetric 1,3-dipolar cycloaddition reactions of nitrones with oxazolidinone derivatives (Figure 16.3) [27a,b,c] Recently, Kiindig et al. [27] had reported that the single coordination site Fe and Ru transition-metal Lewis acids can efficiently promote enantioselective 1,3-dipolar cycloadditions of nitrones with a,p-unsaturated aldehydes and represent a rapid access to substrates of high synthetic potential. The Fe catalyst (81) was found to be an excellent catalyst for 1,3-dipolar cycloaddition reactions between methacrolein and nitrone (83) (Scheme 16.24, Table 16.5). Isox-azolidine (84a) was formed as a single region- and diastereoisomer in excellent... 

Iwasa, S., Ishima, Y., Widagdo, H. S., Aoki, K., Nishiyama, H. (2004). Synthesis of novel chiral bis(2-oxazolinyl)xanthene (xabox) ligands and their evaluation in catalytic asymmetric 1,3-dipolar cycloaddition reactions of nitrones with 3-crotonoyl-2-oxazolidinone. Tetrahedron Letters, 45, 2121-2124. 

MacMillan has described a class of readily available, chiral imidazolidi-nones that act as catalysts in a variety of catalytic asymmetric transformations [89]. The chiral imidazolidinone catalyst 103 was noted to be efficient for the activation of simple a, 5-unsaturated aldehydes towards dipolar cycloaddition reactions via the corresponding iminium intermediate 104 (Scheme 18.20) [90]. With crotonaldehyde (102), the [l,3]-dipolar cycloaddition reaction with nitrone 97 furnished the corresponding endo cycloadduct 105 with high stereoselectivity (endolexo=9A (>, 94% ee). The observed stereoselectivity was consistent with preferential formation of the ( )-isomer 104. 

In addition to this, asymmetric 1,3-dipolar cyclization reactions of nitrones with olefins,40 41 catalytic enantioselective cyanation of aldehydes,42 catalytic enantioselective animation,43 and aza-Michael reactions44 have been reported, and high enantioselectivities are observed. 

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. 

The development and application of catalytic enantioselective 1,3-dipolar cycloadditions is a relatively new area. Compared to the broad application of asymmetric catalysis in carbo- and hetero-Diels-Alder reactions (337,338), which has evolved since the mid-1980s, the use of enantioselective metal catalysts in asymmetric 1,3-dipolar cycloadditions remained almost unexplored until 1993 (5). In particular, the asymmetric metal-catalyzed reactions of nitrones with alkenes has received considerable attention during the past 5 years. 

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. 

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