Enantioselectivity azomethine ylide 1,3-dipolar cycloadditions

When, on the other hand, organocatalyst 133 (possessing a bulky 2,5-diaryl-pyrrole moiety) is applied, product 134 was selectively formed by a highly diastereo- and enantioselective 1,3-dipolar cycloaddition (11 examples, 56-90%, 60-91% ee). This reaction most likely involves activation of the nitroalkene by the thiourea, via the earlier mentioned doubly hydrogen-bonded interaction, followed by a concerted attack of the in situ formed azomethine ylide (this ylide is not activated by nor coordinated to the organocatalyst, because of the bulky, nonbasic pyrrole group, but is most likely formed via a 1,2-prototropic rearrangement [92]). 

Enantioselective 1,3-dipolar cycloadditions employing azomethine ylides and asymmetric catalysis are discussed in the next chapter. The formation of chiral non-racemic pyrrolidine derivatives via dipolar cycloadditions presents an important challenge that has been successfully overcome. The role of catalysis involving different metals is also highUghted. 

Guo and co-workers reported a highly enantioselective 1,3-dipolar cycloaddition of azomethine ylides with p-nucleobase-substituted acrylates as dipolarophiles using 1 mol% of a chiral Cu(I) complex, which provides the first rapid and divergent access to various enantioenriched azacyclic nucleoside analogues in high yields with excellent exo-selectivities and enantioselectivities (Scheme 8) [19]. In addition, other p-heteroarylacrylates such as pyrimidine-, benzimidazole-, imidazole-, benzotriazole-, and indole-substituted acrylates are also suitable... 

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

This chapter deals mainly with the 1,3-dipolar cycloaddition reactions of three 1,3-dipoles azomethine ylides, nitrile oxides, and nitrones. These three have been relatively well investigated, and examples of external reagent-mediated stereocontrolled cycloadditions of other 1,3-dipoles are quite limited. Both nitrile oxides and nitrones are 1,3-dipoles whose cycloaddition reactions with alkene dipolarophiles produce 2-isoxazolines and isoxazolidines, their dihydro derivatives. These two heterocycles have long been used as intermediates in a variety of synthetic applications because their rich functionality. When subjected to reductive cleavage of the N—O bonds of these heterocycles, for example, important building blocks such as p-hydroxy ketones (aldols), a,p-unsaturated ketones, y-amino alcohols, and so on are produced (7-12). Stereocontrolled and/or enantiocontrolled cycloadditions of nitrones are the most widely developed (6,13). Examples of enantioselective Lewis acid catalyzed 1,3-dipolar cycloadditions are summarized by J0rgensen in Chapter 12 of this book, and will not be discussed further here. 

The stereochemistry of 1,3-dipolar cycloadditions of azomethine ylides with alkenes is more complex. In this reaction, up to four new chiral centers can be formed and up to eight different diastereomers may be obtained (Scheme 12.4). There are three different types of diastereoselectivity to be considered, of which the two are connected. First, the relative geometry of the terminal substituents of the azomethine ylide determine whether the products have 2,5-cis or 2,5-trans conformation. Most frequently the azomethine ylide exists in one preferred configuration or it shifts between two different forms. The addition process can proceed in either an endo or an exo fashion, but the possible ( ,Z) interconversion of the azomethine ylide confuses these terms to some extent. The endo-isomers obtained from the ( , )-azomethine ylide are identical to the exo-isomers obtained from the (Z,Z)-isomer. Finally, the azomethine ylide can add to either face of the alkene, which is described as diastereofacial selectivity if one or both of the substrates are chiral or as enantioselectivity if the substrates are achiral. 

Diastereoselective reactions of azomethine ylides with chiral vinyl sulfoxides have also been conducted (Scheme 12.35) (162-164). The 1,3-dipolar cycloaddition of (R)s-p-tolyl vinyl sulfoxide (106) with l-methyl-3-oxidopyridinum (105) gave three of the four possible diastereomers, and one of these isomers 107 was used for the enantioselective synthesis of the (75)-(—)-2a-tropanol 108 (162). 

Grigg and co-workers (383) found that chiral cobalt and manganese complexes are capable of inducing enantioselectivity in 1,3-dipolar cycloadditions of azomethine ylides derived from arylidene imines of glycine (Scheme 12.91). This work was published in 1991 and is the first example of a metal-catalyzed asymmetric 1,3-dipolar cycloaddition. The reaction of the azomethine yhde 284a with methyl acrylate 285 required a stoichiometric amount of cobalt and 2 equiv of the chiral ephedrine ligand. Up to 96% ee was obtained for the 1,3-dipolar cycloaddition product 286a. 

In the area of [3 + 2]-cycloadditions (1,3-dipolar cycloadditions), chiral silver catalysts have been utilized extensively for the enantioselective formation of five-membered rings from prochiral substrates. For example, Zhang and co-workers360 have reported the highly enantioselective Ag(i)-catalyzed [3 + 2]-cycloaddition of azomethine ylides to electron-deficient alkenes. Thus, reaction of ct-imino esters 442 with dimethyl maleate in the presence of catalytic amounts of silver(i) acetate and the chiral bisferrocenyl amide phosphine 443 provided the chiral pyrrolidines 444 with high stereoselectivities and chemical yields (Scheme 131). Only the endo-products were isolated in all cases. 

However, at this stage relatively little progress has been made in research on asymmetric catalytic carbene transfer to imines. In 1995, Jacobsen and Jorgensen reported independently that reaction of ethyl diazoacetate with selected imines can be catalyzed by copper salts [27,28]. In the former case [27], moderate levels of enantioselection were found to be imparted by bisoxazoline ligands associated with the copper catalyst (Scheme 11). The observation of racemic pyrrolidine byproducts in the reaction was taken to support a mechanism of catalysis involving initial formation of a copper-bound azomethine yhde intermediate (Scheme 12 ). Collapse of this intermediate to the optically active aziridine apparently competes with dissociation of the copper to a free azomethine ylide. The latter can react with fumarate formed by diazoester decomposition in a dipolar cycloaddition to afford racemic pyrrolidine. 

Gong and co-workers reported that the bisphosphoric acid (151) catalyzed 1,3-dipolar cycloaddition reactions of buta-2,3-dienoates (147) with azomethine ylides obtained by condensation of the aminoacid ester (149) with the aldehyde (148) to afford 3-methylenepyrrolidine derivatives (150) with excellent enantioselectivity (up to 97% ee) (Scheme 40). ... 

The first chiral thiourea-catalyzed stereoselective 1,3-dipolar cycloaddition of azomethine ylides with nitroalkenes 210 was reported by Gong, et. al., Scheme 3.68 [85], This reaction afforded highly substituted pyrrolidines 212 with high diastereo-selectivities and moderate enantioselectivities. 

The group of Gong and coworkers explored a biomimetic 1,3-dipolar cycloaddition between a-ketoester 79 and benzylamine derivatives 80 with electron-deficient olefins 81a,b to devise a straightforward route to proline derivatives 82 in high yields and enantioselectivities [49]. The proposed biomimetic three-component 1,3-dipolar cycloaddition proceeds as illustrated in Scheme 2.22a. The azomethine ylide B is formed, via a transamination from ketimine ester A, which is in turn prepared from a-ketoesters 79 and benzyl-amine derivatives 80 then, the 1,3-dipolar cycloaddition with electron-poor olefins 81a takes place. For this purpose, the bisphosphoric acid 83 was found to be the catalyst of choice to promote such transformation (Scheme 2.22b). Replacing dimethyl maleate (previously used as deficient olefins) by methyleneindolinones, the same approach could be extended to spirooxindoles synthesis in high yields and... 

In addition to the body of work dedicated to application of chiral Cu(II) catalysts in enantioselective Diels-Alder and hetero Diels-Alder reaction, a number of chiral Cu(II) catalysts have been applied to/developed for alternate cycloaddition methodologies. The majority of examples in this area pertain to 1,3-dipolar cycloadditions of nitrones and azomethine ylides. However, in recent years example of enantioselective Cu(II)-catalyzed [2 + 2) and [4 + 3) cycloadditions have been reported. 

The 3 + 2-cycloaddition reaction of azomethine ylides with c-deficient alkenes produced polysubstituted l- and D-unnatural prolines. Also, phosphoramidite-(7u(OTf)2 complexes catalyse the 1,3-dipolar cycloaddition reactions of azomethine ylides with nitroalkenes to yield exo-tetrasubstituted proline esters." The 1,3-dipolar cycloaddition of non-stabilized azomethine ylides, from iV-alkyl-a-amino acids and aldehydes, with 3-substituted coumarins provides l-benzopyrano[3,4-c]pyrrolidines in good yields and high regio- and stereo-selectivity." The organocatalytic 1,3-dipolar cycloaddition of azomethine ylides, derived from azlactones, with methyleneindolinones produced spirooxindoles with high yields (up to 95%) and high diastereo- (93 7 dr) and enantioselectivity (98% ee). ... 

Most recently, Carretero and co-workers described the first example of the Cu (I)-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with acyclic activated 1,3-dienes (Scheme 13) [25], This cycloadditiOTi occurs selectively at the terminal C=C bmid of the dienes, and the exo-adducts could be obtained with high diastereocOTitrol and excellent enantioselectivity. 

Most recently, Waldmann and co-workers disclosed a cascade transformation to allow the highly diastereo- and enantioselective synthesis of structurally complex 5,5,5-tricyclic products with eight stereocenters, which initiated by copper-catalyzed aerobic oxidation of cyclopentadiene to cyclopentadienone followed by catalytic asynunetric double 1,3-dipolar cycloaddition with azomethine ylides (Scheme 18) [33]. 

In the same year, Wang s group reported the highly enantioselective Cu(l)-catalyzed asymmetric 1,3-dipolar cycloaddition of azomethine ylides with... 

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