Dipolar catalytic enantioselective

Scheme 6.7. Catalytic Enantioselective 1,3-Dipolar Cycloaddition Reactions...

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. 

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. 

Finally, the catalytic enantioselective 1,3-dipolar cycloaddition reaction has recently been developed to be a highly selective reaction of nitrones with electron-deficient alkenes activated by chiral Lewis acids. High levels of regio-, diastereo-, and enantioselectivities can now be reached using catalysts 89 <2000JOC9080>, 90 <2002JA4968>, or 91 <2005JA13386> (Scheme 29). 

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. 

Kobayashi and Kawamura (374) used the catalytic enantioselective 1,3-dipolar cycloaddition for the synthesis of an optically active p-lactam (Scheme 12.85). The... 

Catalytic enantioselective 1,3-dipolar cycloaddition reactions of nitrones 00CC1449. 

Mish, M.R., Gnerra, E.M., and Carreira, E.M., Asymmetric dipolar cycloadditions of Me3SiCHN2. Synthesis of a novel class of amino acids azaprolines, J. Am. Chem. Soc. 119 (35), 8379, 1997. Kim, Y., Singer, R.A., and Carreira, E.M., Total synthesis of macrolactin A with versatile catalytic, enantioselective dienolate aldol addition reactions, Angewandte Chemie-Intemational Edition 37 (9), 1261, 1998. 

Dipolar cycloadditions between nitrones and alkenes are most useful and convenient for the preparation of isoxazolidine derivatives, which are readily converted to 1,3-amino alcohol equivalents under mild reducing conditions (Tufariello 1984, Torssell 1988). In spite of the importance of chiral amino alcohol units for the synthesis of biologically important alkaloids, amino acids, 3-lactams, and amino sugars, etc. (for a review see Frederickson 1997), catalytic enantioselective 1,3-dipolar cycloadditions remain relatively unexplored (Seerden et al. 1994, 1995, Gothelf and Jorgensen 1994, Gothelf et al. 1996, Hori et al. 1996, Seebach et al. 1996, Jensen et al. 1997). Catalytic enantioselective... 

Hydroxyethyl (3-lactam derivative was synthesized using the present reactions (scheme 17). Isoxazolidine derivative 37, prepared via the catalytic enantioselective 1,3-dipolar cycloaddition, was treated with methoxymagnesium iodide (Evans et al. 1985) to give methyl ester 38. Reductive N-O bond cleavage and deprotection of... 

Another successful catalytic enantioselective 1,3-dipolar cycloaddition of Qf-diazocarbonyl compounds using phthaloyl-derived chiral rhodium(II) catalysts has been demonstrated [ill]. Six-membered ring carbonyl ylide formation from the a-diazo ketone 80 and subsequent 1,3-cycloaddition with DMAD under the influence of 1 mol % of dirhodium(II) tetrakis[M-benzene-fused-phthaloyl-(S)-phenylvaline], Rh2(S-BPTV)4 101 [112], has been explored to obtain the cycloadduct 102 in up to 92% ee (Scheme 31). 

Simonsen KB, Bayon P, Hazell RG, Gothelf KV, Jprgensen KA (1999) Catalytic enantioselective inverse-electron demand 1,3-dipolar cycloaddition reactions of nitrones with alkenes. J Am Chem Soc 121 3845-3853... 

Jensen KB, Roberson M, J0rgensen KA (2000) Catalytic enantioselective 1,3-dipolar cycloaddition reaction of cyclic nitrones a simple approach for the formation of optically active isoquinoline derivatives. J Org Chem 65 9080-9084... 

Iwasa and Nishiyama reported catalytic enantioselective 1,3-dipolar cycloaddition reactions of nitrones using chiral Mg(II) complexes (Scheme 4.7) [5]. They synthesized chiral tridentate bis(2-oxazolinyl)xanthene ligands (Xabox, 19) and the chiral environments were evaluated in the 10mol% Xabox-Mg(Cl04)-(H20)6-catalyzed enantioselective 1,3-dipolar cycloaddition of nitrones (1 equiv) with 3-crotonyl-2-oxazolidinone (1 equiv). The reactions of (16) and (17) in dichloromethane at 10 °C proceeded smoothly to give the corresponding adduct (18) with 92% ee and an endo exo ratio of > 99 1. 

Jorgensen et al reported catalytic enantioselective 1,3-dipolar cycloaddition reactions of azomethine ylides with alkenes (Scheme 4.24) [24]. In their method. 

A rather unexpected discovery was made in connection to these investigations [49]. When the 1,3-dipolar cycloaddition reaction of la with 19b mediated by catalyst 20 (X=I) was performed in the absence of MS 4 A a remarkable reversal of enantioselectivity was observed as the opposite enantiomer of ench-21 was obtained (Table 6.1, entries 1 and 2). This had not been observed for enantioselective catalytic reactions before and the role of molecular sieves cannot simply be ascribed to the removal of water by the MS, since the application of MS 4 A that were presaturated with water, also induced the reversal of enantioselectivity (Table 6.1, entries 3 and 4). Recently, Desimoni et al. also found that in addition to the presence of MS in the MgX2-Ph-BOX-catalyzed 1,3-dipolar addition shown in Scheme 6.17, the counter-ion for the magnesium catalyst also strongly affect the absolute stereoselectivity of the reac-... 

For the activation of a substrate such as 19a via coordination of the two carbonyl oxygen atoms to the metal, one should expect that a hard Lewis acid would be more suitable, since the carbonyl oxygens are hard Lewis bases. Nevertheless, Fu-rukawa et al. succeeded in applying the relative soft metal palladium as catalyst for the 1,3-dipolar cycloaddition reaction between 1 and 19a (Scheme 6.36) [79, 80]. They applied the dicationic Pd-BINAP 54 as the catalyst, and whereas this type of catalytic reactions is often carried out at rt or at 0°C, the reactions catalyzed by 54 required heating at 40 °C in order to proceed. In most cases mixtures of endo-21 and exo-21 were obtained, however, high enantioselectivity of up to 93% were obtained for reactions of some derivatives of 1. 

Dipolar cydoadditions are one of the most useful synthetic methods to make stereochemically defined five-membered heterocydes. Although a variety of dia-stereoselective 1,3-dipolar cydoadditions have been well developed, enantioselec-tive versions are still limited [29]. Nitrones are important 1,3-dipoles that have been the target of catalyzed enantioselective reactions [66]. Three different approaches to catalyzed enantioselective reactions have been taken (1) activation of electron-defident alkenes by a chiral Lewis acid [23-26, 32-34, 67], (2) activation of nitrones in the reaction with ketene acetals [30, 31], and (3) coordination of both nitrones and allylic alcohols on a chiral catalyst [20]. Among these approaches, the dipole/HOMO-controlled reactions of electron-deficient alkenes are especially promising because a variety of combinations between chiral Lewis acids and electron-deficient alkenes have been well investigated in the study of catalyzed enantioselective Diels-Alder reactions. Enantioselectivities in catalyzed nitrone cydoadditions sometimes exceed 90% ee, but the efficiency of catalytic loading remains insufficient. 

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]. 

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