Azomethine ylides, enantioselective

It is well known that the use of a synthetic equivalent of azomethine ylide, the thiazolium ylide, a known synthon for the simple azomethine dipole, undergoes cycloadditions with higher regioselectivity than the parent ylide <1994JOC4304, 1994JOC2773>. In order to control the enantioselectivity of the reaction, an Evans oxazolidionone was incorporated into the acrylate dipolarophile as in Scheme 71. The cycloaddition was carried out by reaction of 4 equiv of the acrylate with the thiazolium salt to afford the diastereomeric tricyclic adduct 27 (Scheme 71) <2002BMC3509>. 

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 above azomethine ylide cycloadditions have been extended to an enantioselective version involving amino alcohols both as chiral ligands and amine bases. Thus, reactions of the N-metalated azomethine yhdes derived from achiral methyl 2-(arylmethyleneamino)acetates, cobalt(II) chloride [or manganese(II) bromide], and chiral amino alcohols, 1 and 2 equiv each, with methyl acrylate as solvent have been performed to provide the enantiomer-enriched pyrrolidine-2,4-dicarboxylates with the enantioselectivities of up to 96% enantiomeric excess (ee) (128,129). However, a large excess of the metal ions and the chiral source (ligand and base) have to be employed. 

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). 

These principles of activation and induction of asymmetry apply primarily to reactions of nitrones. For the reactions of other 1,3-dipoles, the catalyst-induced control of the enantioselectivity may in some cases be achieved by other principles. For the metal-catalyzed reactions of azomethine ylides, carbonyl ylides, and nitrile... 

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. 

The [3+2] cycloadditions are the most prolific of all the silver-catalyzed cycloadditions. The unique affinity of silver for imines has facilitated the development of highly efficient and enantioselective cycloadditions of azomethine ylides to alkenes. Judicious choice of reaction conditions is crucial in achieving high yields for different substitution patterns. 

Zhou also reported a series of related P,S-ferrocenyl ligands and their use in the [3+2] cycloaddition of aryl-substituted azomethine ylides with A-phenylmalei-mide.52 While these silver complexes were able to efficiently catalyze the reaction, the enantioselectivity was lower than in the protocol described above. 

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. 

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]). 

Studies of different cinchona alkaloids as the chiral Bronsted bases and a metal salt showed that hydrocinchonine lh (Scheme 10.13) and AgF were the most effective combination. The scope of the [3 + 2] cydoaddition of azomethine ylides and alkenes was investigated. Selected examples are shown in Scheme 10.14. High yields and moderate enantioselectivities were obtained from a variety of a-imino esters. It was worth mentioning that most of the pyrrolidine derivatives 11 obtained from tert-butyl acrylate were solids that could be enantiomerically enriched by crystallization. 

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). ... 

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. 

---