Azomethine ylides enantioselective additions

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. 

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. 

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... 

Enantioselective total synthesis of ((47J,5iS)-5-Amino-4-(2,4,5-tri-fluorophenyl) cyclohex- l-enyl)-(3-(trifluoromethyl)-5,6-dihydro-[l, 2,4]tri-azolo[4,3-a]pyrazin-7(877)-yl)methanone ABT-341 (708), a DPP4 (dipeptidyl peptidase IV) inhibitor, has been completed in diphenylprolinol silyl ether (707), in the one-pot, multicomponent, reaction of nitroalkene (704), acetaldehyde (703), vinyl phosphonate (706) and amine (705) (Scheme 178) A novel, catalytic, asymmetric Michael addition of azomethine ylide (710) with p-substituted tetraethyl alkyhdene bisphosphates (709) has been realised in the presence of a chiral copper(I)/TF-Bipham-Phos (712) complex. This system provided enantioenriched unnatural i -amino acid derivatives (711) containing gem-bisphosphonates in high yields with... 

---