Azomethine enantioselective cycloaddition

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 [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. 

Hou and coworkers have developed a remarkable methodology for highly enantioselective cycloaddition of azomethine ylides (349) with nitroalkenes (353) [109]. CuC104/ligand (354) or (357) complexes both provide the desired pyrrolidine cycloadducts (355) or (358) excellent enantioselectivities. However, CuCl04/(354)... 

Although considerable improvements have been made for endo-selective cycloadditions of azomethine imines, methods for exo and enantioselective cycloaddition of azomethine imines were relatively scarce. By employing novel, multifunctional primary amine catalysts 145 derived from cinchona alkaloids in the presence of triisopropylbenzene sulfonic acid (TIPBA) 146 as cocatalyst, Chen and coworkers developed the first organocatalytic, highly exo-selective, and enantioselective 1,3-DC reaction of cyclic enones 142 and azomethine imines 143 in 2007 [53]. The additional and synergistic hydrogen-bonding interaction of catalyst and 1,3-dipole is essential for enantiocontrol, and excellent stereoselectivities were achieved for a broad scope of substrates (dr > 99 1, up to 95% ee) (Scheme 2.37). 

The first Lewis acid-catalyzed exo and enantioselective cycloaddition of azome-thine imines with pyrazolidinone acrylates 147 was developed by Sibi in 2008 [54]. By using in situ formed copper(II)/bisoxazoline 25 complex as the catalyst, cycloadducts 149 derived from a variety of azomethine imines 148 were prepared in good to high yields with moderate to good exo selectivity and high enantioselectivity (Scheme 2.38). 

Sibi, M. R, Rane, D., Stanley, L. M., Soeta, T. (2008). Copper(II)-catalyzed exo and enantioselective cycloadditions of azomethine imines. Organic Letters, 10, 2971-2974. 

In the last case, the enantioselective cycloaddition of the azomethine ylides was estabhshed by Antonchick and Waldmann. Use of substoichiometric amounts of copper(I) salts in the presence of a stereodirecting ligand such as 182 and base led to the formation of two diastereomeric [6+3] cycloaddition products 183 (Scheme 6.47) [111]. 

Scheme 11.9 NHC-Ag-catalyzed enantioselective cycloaddition of azomethines and acrylates.

In contrast to tran -selectivity (cndo-selectivity) of the Ni (n)-catalyzed reactions, Sibi et al. reported ciiy-selective (exo-selective) and highly enantioselective cycloadditions between -cyclic azomethine imines and 2-acryloyl-l-benzyl-5,5-dimethyl-3-pyrazohdinone catalyzed by the bisoxazoline-Cu(II) complex (10mol%) consisting of Cu (OTf>2 and (15,2I )-l-amino-2-indanol-deiived bisoxazoline (INDABOX) (Table 7.2) [12]. Interestingly, the use of additional chiral Lewis acid complexes prepared from INDABOX and Mg(II), Zn(II), or Ni(II) salts led to tmns-selective (emio-selective) cycloadditions of azomethine imine. The INDABOX-Mg(OTf)2- and INDABOX-Zn... 

Grigg et al. have found that chiral cobalt and manganese complexes are capable of inducing enantioselectivity in 1,3-dipolar cycloaddition reactions of azomethine... 

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 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. 

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