Catalytic asymmetric alkylation of imines

Although several excellent examples of the catalytic asymmetric alkylation of imines have been reported, especially in the past few years, the scope of the reactions is still limited with regard to substrate generality, experimental simplicity, catalyst loading, and the enantiomeric purity of the isolated products. Research in this field has just started and further development can be expected in the near future. 

Two main strategies for the catalytic asymmetric alkylation of imines are (a) chiral Lewis acid approach and (b) chiral nucleophilic approach. 

Catalytic, Asymmetric Alkylation Of Imines Ferraris, D. Tetrahedron 2007, 63, 9581. 

Scheme 6.18. Three-component Zr-catalyzed asymmetric alkylation of imines by alkylzincs leads to the formation of optically enriched amines not accessible by alternative methods such as catalytic hydrogenation.

In addition, in 2(X)4 Mamoka and co-workers [72] synthesized a recyclable fluorous chiral phase-transfer catalyst which was successfully applied for the catalytic asymmetric alkylation of a glycine-imine derivative followed by extractive recovery of the chiral phase-transfer catalyst using fluorous solvent. Later, in 2010 Itsuno and co-workers [73] published a new type of polymer-supported quarternary ammonium catalysts based on either cinchona alkaloids or Maruoka s-type catalyst bound via ionic bonds to the polymeric sulfonates. 

The more recently reported Zr-catalyzed asymmetric alkylation of aliphatic imines is shown in Scheme 6.18 [58]. Several important principles merit specific mention. (1) The catalytic asymmetric protocol can readily be applied to the synthesis of non-aryl im-... 

To enhance the efficiency of the cyanide addition, these workers subsequently reported a three-component asymmetric synthesis of amino nitriles that avoids the use of the previously mentioned undesirable stannane [74], Thus, as illustrated in Scheme 6.23, treatment of the requisite aniline and aldehyde with HCN (toxic but cheap and suitable for industrial use) at —45°C in the presence of 2.5 mol% 65 leads to the formation of 67 with 86 % ee and in 80 % yield. As was mentioned above in the context of catalytic asymmetric three-component alkylations of imines (see Scheme 6.18), the in situ procedure is particularly useful for the less stable aliphatic substrates (cf. 71—73, Scheme 6.23). The introduction of the o-Me group on the aniline is reported to lead to higher levels of asymmetric induction, perhaps because with the sterically less demanding aliphatic systems, the imine can exist as a mixture of interconverting cis and trans isomers. 

The tremendous success in the catalytic asymmetric addition of organozinc reagents to aldehydes spurred Itsuno and co-workers to examine the reactivity of diethylzinc with silyl imines in the presence of chiral amino alcohols and diols. Unfortunately, this type of azomethine function failed to react [23a]. The use of activated N-acyl- and iV-phosphinoylimines turned out to be crucial as evidenced by the following reports on the alkylation of these functions using di-... 

As part of an ongoing research program directed toward the use of chiral aziridines in asymmetric synthesis [36], Andersson, Tanner and co-workers have recently reported the detailed results of their own findings in the field of catalytic asymmetric dialkylzinc alkylation of imines [37dj. Tanner et al. had previously communicated their success in the catalytic asymmetric addition of organolith-ium reagents to imines with C2-symmetric bis(aziridines) [37a, 37b]. This was followed by a preliminary report on the use of aziridino alcohols as well as simple aziridines for the addition of diethylzinc to M-diphenylphosphinoylimines [37c]. The most recent report is an extension of this study, and includes the detailed preparation of the ligands [37d]. 

The aziridino alcohols that have been prepared and tested as chiral promoters for the catalytic asymmetric dialkylzinc alkylation of imines are shown in Fig. 4. The authors have investigated three different approaches to obtain the ligands in enantiomerically pure form (1) the use of the chiral pool, (2) the Sharpless asymmetric aminohydroxylation, and (3) the Sharpless asymmetric dihydroxylation. The starting materials for the preparation of the aziridino alcohols 30, 31a-h, 32a,b, and 33 were the readily available amino acids L-serine, L-threonine, and aZZo-L-threonine. 

An amino ether 46, presumably derived from (+)-3-carene [( + )-40], has been used for asymmetric alkylation of azaenolates via imines (SectionD.1.1.1,4.1., ref 40). No details were given on the synthesis of 46, but it can be prepared by methylation of the corresponding amino alcohol which was probably obtained from the epoxide of ( + )-3-carene by ring opening with trimethylsilyl azide, followed by catalytic hydrogenation41,... 

Lectka et al. reported on a practical methodology for the catalytic, asymmetric synthesis of (3-lactams 203. Compound 203 results from the reaction of ketenes (or derived zwitterionic enolates) 201 and imines 202 via C—N alkylative cyclization using benzoylquinine as a chiral catalyst and a proton sponge as the stoichiometric base with moder-ate-to-good yield and excellent diastereoselectivity and enantioselectivity (Scheme 40.41). " ... 

Some phase-transfer catalytic asymmetric alkylation reactions of glycine imine derivatives have been explored to access natural products and biologically active compounds. For example, by employing an enantioselective phase-transfer catalytic alkylation, Kim et al. accomplished the first asymmetric total synthesis of the naturally occurring phenanthroindolizidine alkaloid (—)-antofine (Scheme 12.2) [102]. The key feature of this synthesis is the creation of the stereogenic center by reacting 65a with electrophile 66 in the presence of the dimeric catalyst 28 under the phase-transfer conditions. 

The studies summarized above clearly bear testimony to the significance of Zr-based chiral catalysts in the important field of catalytic asymmetric synthesis. Chiral zircono-cenes promote unique reactions such as enantioselective alkene alkylations, processes that are not effectively catalyzed by any other chiral catalyst class. More recently, since about 1996, an impressive body of work has appeared that involves non-metallocene Zr catalysts. These chiral complexes are readily prepared (often in situ), easily modified, and effect a wide range of enantioselective C—C bond-forming reactions in an efficient manner (e. g. imine alkylations, Mannich reactions, aldol additions). 

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... 

The Zr-catalyzed asymmetric alkylation shown in Eq. (2) [8] illustrates two important principles (1) The catalytic asymmetric protocol can be readily applied to the synthesis of non-aryl imines to generate homochiral amines that cannot be prepared by any of the alternative imine or enamine hydrogenation protocols. (2) The catalytic amine synthesis involves a three-component process that includes the in situ formation of the imine substrate, followed by its asymmetric alkylation. This strategy can also be readily applied to the preparation of arylamines. The three-component enantioselective amine synthesis suggests that such a procedure maybe used to synthesize libraries of homochiral amines in a highly efficient and convenient fashion. 

Scheme 4.1 Synthesis of a-alkyl-a-amino acids via asymmetric phase-transfer catalytic alkylation ofbenzophenone imine glycine ester (A).

---