Asymmetric Addition to Imines

Regarding the reagent control asymmetric addition to imines, there were three reports with aldo-imines. Based on our best knowledge, no asymmetric addition to ketimine was reported prior to our work (vide infra). 

At around the same time, other groups further reported the deprotonation-activation of malonates for the asymmetric addition to imines. Various malonates and aromatic V-acyl imines produced high yielding adducts with excellent stereoselectivities [87, 88]. 

Carbon-Carbon Bond-Forming Reactions TABLE 9.32. ASYMMETRIC ADDITION TO IMINES"... 

Recent advances in catalytic asymmetric addition to imines and other C=N systems have been reviewed.68... 

Examples in Table 3 highlight 1,2-asymmetric additions to imine derivatives. Tanaka [25] reported the addition of alkyl Grignard reagents to the isoquinolines to yield a single enantiomer (see Table 3, entry 1). 

Articles summarizing current state of asymmetric addition to imines and highlighting Mannich reaction are available. Special attention has also been devoted the employment of organocatalysts for the Mannich reaction. 

The nucleophiles discussed above can also react with the C=N group and the final section of this chapter describes the many recent advances in the catalytic asymmetric additions to imines using both metal complexes and also organocatalysts. 

Nucleophilic additions to imines are generally more challenging than additions to carbonyls, owing to the lower electrophilicity of the imine and the greater propensity for a-deprotonation. Furthermore, stereoselective processes may be complicated by the presence of synlanti imine isomers. Nevertheless, the direct, enantioselective synthesis of substituted amines is an attractive goal and, while catalytic asymmetric additions to imines are less developed than the corresponding... 

Scheme 24.21 Asymmetric addition to imines catalysed by axially chiral dicarboxylic acids.

Recent developments in the catalytic asymmetric cyanation of ketimines. (c) T. Vilaivan, W. Bhanthumnauin, Y. Sritana-Anant, Curr. Org. Chem. 2005, 9, 1315-1392. Recent advances in catalytic asymmetric addition to imines and related C=N systems, (d) S. J. Connon, Angew. Chem. Int. Ed. 2008,47,1176-1178. The catalytic asymmetric Strecker reaction ketimines continue to join the fold. 

Asymmetric Additions to Imines A Straightforward Route to iV,X-Acetals... 

For activation of more unconventional substrates in the asymmetric addition to imines, Ricci and coworkers [13d] investigated the utility of asymmetric phospho-nylation. The hydrophosphonylation of imines was achieved to provide a-amino... 

Asymmetric addition to ketimine in a reagent controlled manner has seldom been reported, even by 2008. When we investigated the potential for tbis asymmetric addition around 1992, there were no known examples. In 1990, Tomioka et al., reported the first asymmetric addition of alkyl lithium to N-p-methoxyphenyl aldo-imines in the presence ofa chiral (3-amino ether with 40-64% ee [8] (Scheme 1.11). In 1992, Katritzky reported the asymmetric addition of Et2Zn to in situ prepared N-acyl imine in the presence of a chiral (3-amino alcohol with 21-70% ee [15] (Scheme 1.12). In the same year, Soai et al., reported the asymmetric addition of dialkylzinc to diphenylphosphinoyl imines in the presence of chiral (3-amino alcohols with 85-87% ee [16] (Scheme 1.13). These three reports were, to the best of... 

Catalytic asymmetric cyanide addition to imines constitutes an important C—C bondforming reaction, as the product amino nitriles may be converted to non-proteogenic a-amino acids. Kobayashi and co-workers have developed two different versions of the Zr-catalyzed amino nitrile synthesis [73]. The first variant is summarized in Scheme 6.22. The bimetallic complex 65, formed from two molecules of 6-Br-binol and one molecule of 2-Br-binol in the presence of two molecules of Zr(OtBu)4 and N-methylimidazole, was proposed as the active catalytic species. This hypothesis was based on various NMR studies more rigorous kinetic data are not as yet available. Nonetheless, as depicted in Scheme 6.22, reaction of o-hydroxyl imine 66 with 5 mol% 65 and 1—1.5 equiv. Bu3SnCN (CH2C12, —45 °C) leads to the formation of amino nitrile 67 with 91 % ee and in 92 % isolated yield. As is also shown in Scheme 6.22, electron-withdrawing (— 68) and electron-rich (—> 69), as well as more sterically hindered aryl substituents (— 70) readily undergo asymmetric cyanide addition. 

Sect. 3.2). However, this approach is limited to the few trialkylboranes that are easily available and cheap since only one of the three alkyl group is transferred. By using a triethylborane as a chain transfer reagent, the reaction could be extended to alkyl iodides as radical precursors. Bertrand [94,114] and Naito [95,97] reported both the use of triethylborane for the tin-free addition of alkyl iodides to imines. A typical example for a tentative of asymmetric addition to a glyoxylate imine is depicted in Scheme 50 (Eq. 50a). More recently additions to isatin imines were reported (Eq. 50b) as well as addition to 2H-aziridine-3-carboxylates by Lemos [100] and Somfai [101] (Eq. 50c). 

Since then, optically active a-aminophosphonates have been obtained by a variety of methods including resolution, asymmetric phosphite additions to imine double bonds and sugar-based nitrones, condensation of optically active ureas with phosphites and aldehydes, catalytic asymmetric hydrogenation, and 1,3-dipolar cycloadditions. These approaches have been discussed in a comprehensive review by Dhawan and Redmore.9 More recent protocols involve electrophilic amination of homochiral dioxane acetals,10 alkylation of homochiral imines derived from pinanone11 and ketopinic acid,12 and alkylation of homochiral, bicyclic phosphonamides.13... 

Optically active a-amino acids are prepared by a cyanide addition to imines, known as the Strecker reaction. Several organobase catalysts and metal complex catalysts have been successfully applied to the asymmetric catalytic Strecker amino... 

As the follow up to our studies in connection to the development of Ti-cat-alyzed cyanide additions to meso epoxides [4], we developed the corresponding catalytic enantioselective additions to imines [5]. A representative example is shown in Scheme 1 chiral non-racemic products maybe readily converted to the derived cx-amino acids (not available through catalytic asymmetric hydrogenation methods). In these studies, we further developed and utilized the positional optimization approach effected by examination of parallel libraries of amino acid-based chiral ligands (e.g., 1 and 2). Thus, the facile modularity of these ligands and their ease of synthesis were further exploited towards the development of a new catalytic enantioselective method that delivers various ar-... 

Several other asymmetric Mannich-type processes have been described. Propargyl alcohols (11) undergo an addition to imines (12), to give 2-acylallylic carbamates (13), using an oxovanadium catalyst.28 The reaction always gave the (Z)-enone, but a trial with a chiral propargyl alcohol showed virtually no enantioselectivity. 

Fig. 2 (a) Earlier efforts to design asymmetric additions to imino compounds required two separate modifications to substituents of the C=N bond to accomplish both activation and stereocontroi. (b) With chiral A-acyihydrazonc acceptors, the carbon branch (R1) of the imine may be varied freely, enabling improved versatility... 

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