Iminoesters azomethines

Cossio and Linden et al. studied the reaction of aryl iminoester-derived azomethine ylides 65 with 2- and 1,2-disubstituted nitroalkenes 66 using silver acetate and triethylamine in acetonitrile (Scheme 2.18).35 The product 3-nitropyrrolidines were formed in yields of 24—69% with excellent regioselectivity. These findings mirrored earlier work by Toke et al.36 Unfortunately, diastereoselectivity was generally in the 1 1—4 region. Only in two cases where yields were low were the products formed in a 2 98 ratio. Lithium perchlorate was able to catalyze the reaction as well with similar yields. Remarkably, the diastereoselectivity with lithium perchlorate in some cases resembled that obtained with silver acetate and in others was reversed. Cossio also reported the stereoselective reaction of phenyl isocyanates with azomethine ylides 65 under the same conditions.37 These reactants combined to give the expected products as single stereoisomer in 30-50% yield. 

While virtually all of the research described above has focused on the inter-molecular cycloaddition of azomethine ylides, the intramolecular process holds considerable promise for the synthesis of polycyclic natural products. The Pfaltz group reported an intramolecular catalytic asymmetric cyclization of aryl iminoesters 112 using a complex of silver acetate with PHOX type ligand 100 (Scheme 2.29,... 

The scope of the silver-catalyzed [3+2] cycloaddition is not limited to amino acid-derived iminoesters. Grigg has reported the use of aminophosphane-derived azomethine ylides in the cycloaddition to afford the corresponding phosphonate-substituted pyrrolidines (Scheme 2.36).62 The diastereoselectivity of these cycloadditions is not inferior to those of standard amino acid-derived imines. 

Hoveyda et al. [262] prepared different N-aryhnaleimidobenzoic acids linked to SASRIN resin, whose double bond present in the maleimido moiety could act as a convenient dipolarophile in cycloaddition reactions. Thus, solution-generated a-iminoesters (from different aromatic aldehydes and aminoesters) were reacted vdth the supported maleimides (158) under Tsuge [263] conditions. Formation of the expected syn-endo cycloadduct (160) was observed after only 1 h at room temperature (Scheme 33). From structure-reactivity analysis, the authors concluded that the cycloaddition reaction is more sensitive to steric then to electronic factors on the azomethine yhde counterpart. The advantage of this procedure stems essentially from the fact that the iminoesters (159) are formed in situ. Aldehydes containing a-hydrogens could also be employed. Moreover, the resin in this case also plays the role of a protective group, because, in contrast with N-alkyl and N-aryl (see above) maleimides, N-unsubstituted maleimide is not suitable for 1,3 dipolar cycloadditions. 

The cycloaddition of in sitM-generated azomethine yhdes with electron-deficient alkenes is a useful method for the generation of stereodefined, substituted pyrrolidines, and there has been some recent interest in the development of a catalytic asymmetric variant. While a variety of methods for the generation of azomethine ylides have been developed, treatment of an a-iminoester (8.200) with an amine base in the presence of metal salts is the process most commonly employed in the asymmetric variant, which generally uses an enantiomerically pure metal complex of copper, silver or zinc to give an N-metallated ylide (8.201) (Figure 8.6). ... 

Bis-oxazolines of much use in both the Diels-Alder and nitrone cycloadditions, have also been shown, by j0rgensen and coworkers, to be good ligands in the azomethine ylide cycloaddition. In particular, the zinc complex formed with Bu-BOX ligand (8.68) and zinc(II) triflate has been used to effect good to high ees in the reaction of ylides generated from iminoesters such as (8.202) with acrylates. 

Pyrrolidinofullerenes are probably the most widely used fullerene derivatives because of their stability, versatility, and the availability of reactants. Their synthesis is based on the 1,3-dipolar cycloaddition of azomethine ylides formed by thermal treatment from aldehydes and amino acids [54, 55] or from iminoesters [56, 57], The latter lacks selectivity since it affords a diastereomeric mixture (cis and trans) of 2,5-disubstituted pyrrolidinofullerenes. 

On the other hand, the use of the suitable combination of a metal salt, chiral ligand, and base promotes at low temperature the formation in situ of chiral A-metalated azomethine ylides from the corresponding iminoester and the subsequent selective cycloaddition onto the fullerene cage. Thus, the P,S chiral ligand Fesulphos along with copper(II) acetate directs the addition toward the formation of the stereoisomer (25, 55)-2-alkoxycarbonyl-5-arylpyrrolidino[3,4 l,2][60]fullerene with complete cis diasteroselectivity and enantiomeric excesses up to 93% (Scheme 34.9). 

Nowadays, many methods are available to generate azomethine ylides, but the in situ metalation of iminoesters to form metalloazomethine dipoles has become the most widely used approach. In their cycloaddition, the coordination of iminoester to the metal catalyst happens initially, which can lead to the formation of the metalloazomethine dipole intermediates. Then, this species reacts with dipolarophile to afford the zwitterionic species, from which the cycloaddition product can be obtained via intramolecular cyclization (Scheme 2.2) [4],... 

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