Asymmetric alkylation of imines

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 contrast to the variety of chiral auxiliaries which have been used in the asymmetric alkylation of imine-derived azaenolates (see Section 1.1.1.4.1Table 7), alkylations of the hydrazone analogues employ mainly (-)-(S)-l-amino-2-methoxymethylpyrrolidine (SAMP) and its opti-cal antipode (RAMP). r A oCH, O ... 

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. 

Table 7.4 a,a-Dialkylamino acid derivatives by asymmetric alkylation of imines 40a and 40b utilizing salen-Cu(ll) complex 39c. 

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

The basic concept, although most likely not the detailed mechanism, of the Enders asymmetric induction follows from the chelation-controlled asymmetric alkylation of imine anions introduced by Meyers and Whitesell. The hydrazones derived from either the (5)- or the (/ )-enantiomer of iV-amino-2-methoxymethylpyrrolidine (SAMP and RAMP, derived from the amino acid proline) can be converted to anions that undergo reaction with a variety of electrophiles. After hydrolysis of the product hydrazones, the alkylated ketones can be obtained with good to excellent levels of optical purity (Scheme 19). 

Asymmetric alkylation of imines has been employed most frequently for the construction of chiral amino moieties involved in the syntheses of nitrogen heterocycles and amino acids [17]. This approach is also useful for fluorinated amino acid synthesis as shown in Scheme 9.7. Mannich reaction of enolate with imino ester 23 in the presence of L-proline gives a-amino esters 24 and 25 enantio-and diastereoselectively [18]. 

In seeking an efficient, economic, and scaleable route to the new potent nonnucleoside HIV-1 reverse transcriptase inhibitor 16 (L-738,372) [2a], process chemists at the Merck Research Laboratories have significantly contributed to the field of asymmetric alkylation of imines. Huffman and co-workers have reported a very efficient asymmetric route to 16 via the addition of a lithium acetylide to the cyclic N-acylketimine 14 in the presence of the lithium alkoxide of the alkaloid quinine as a stoichiometric chiral additive (Scheme 9) [31aj the previous route to the inhibitor 16 included a resolution step [31bj. Whereas other types of chiral additives were screened (e.g., diamines, diethers), only P-ami-no alkoxides were enantioselective. The search for readily available amino alcohols was dictated by the necessity of developing a practical process. The commer-... 

Copper-Catalyzed Asymmetric Alkylation of Imines with Dialkylzinc and Related Reactions Yamada, K.-i. Tomioka, K. Chem. Rev. 2008, 108,2874. 

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

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. 

Figure 3. The tight ion pair 28 in the asymmetric alkylation of the O Donnell imine 23.

In 2007, Maruoka et al. introduced chiral dicarboxylic acids consisting of two carboxylic acid functionalities and an axially chiral binaphthyl moiety. They applied this new class of chiral Brpnsted acid catalyst to the asymmetric alkylation of diazo compounds withA-Boc imines [91]. The preparation of the dicarboxylic acid catalysts bearing aryl groups at the 3,3 -positions of the binaphthyl scaffold follows a synthetic route, which has been developed earlier in the Maruoka laboratory [92]. 

Asymmetric alkylation of benzylamine via the imine 6A, with ( + )-D-camphor (5 A) as chiral auxiliary is possible. Deprotonation with butyllithium and subsequent alkylation with haloalkanes, (R X) afforded the alkylated imines 7 A with reasonable yield but variable diastereo-selectivity. The diastereoselectivity depends strongly on the haloalkane with methoxy-substi-tuted halomethylbenzenes moderate to good diastereoselectivity (d.r. 80 20-90 10) is obtained, however, with haloalkanes or 3-halopropenes only low optical purities (< 50%) were observed. 

Asymmetric alkylation of aldehydes is possible via enamines or azaenolates of imine derivatives (see Section D. 1.1.1.4.). Alkylation is also possible via enol ethers or esters (see Section 1.1.1.3.1.2.), although the use of these methods for asymmetric synthesis has not yet been explored. 

Numerous chiral amines are reported to be useful in the asymmetric alkylation reaction of carbonyl compounds via their imine derivatives (see Section 1.1.1.4.1.)2,4. The asymmetric alkylation of chiral imines was first reported using simple, commercially available amines such as a-methylbenzeneethanamine (amphetamine)1, benzeneethanamine1 5 and exo-l, 7,7-trimethyl-bicyclo[2.2.1]heptan-2-amine (isobomylamine). In the case of cyclohexanone alkylation using these chiral auxiliaries, enantiomeric excesses of up to 72% were obtained1. 

In contrast to earlier known imines, those imines derived from a-(methoxymethyl)benzene-ethanamine, which allow formation of a rigid chelate by additional coordination of the lithium with the methoxy group, enabled the preparation of a-alkylated cyclic ketones in very high enantiomeric excesses (90-99% ee)7,8. However, alkylations of imines derived from medium ring ketones were accomplished in 30-82% ee9. The alkylation of acyclic ketones was performed with enantiomeric excesses of more than 75 % and, in the case of the imine derived from 4-heptanone, proceeded with complete asymmetric induction10. 

In addition, the /erf-butyl esters of valine and tert-leucine are excellent chiral auxiliaries in asymmetric alkylation of their imines. These chiral auxiliaries are preferentially used in the alkylation of cyclic ketones (73 to >99% ee)17 and /i-oxo esters (44 to >99% ee)18,, 9 and the absolute configuration of the products can be safely predicted. 

The highly selective alkylation reaction of chiral imines, which in some cases occurs under complete asymmetric induction, as well as the simple introduction and recovery of the chiral auxiliaries, ensures that asymmetric alkylation of carbonyl compounds via their corresponding imines is a valuable tool in organic chemistry. 

Table 7. Chiral Auxiliaries Used in the Asymmetric Synthesis of Carbonyl Compounds by Alkylation of Imines...

Quite recently, there has been significant expansion and development in the alkylation of imines with organozinc reagents using chiral Lewis acid catalysts. In 2000, Tomioka and co-workers reported a copper(II)-chiral amidophos-phine 4-catalyzed asymmetric process for the addition of diethylzinc to N-sul-fonylimines (Scheme 2) [8]. Excellent enantioselectivities (90-94%) and yields (83-99%) were obtained in reactions of N-sulfonylimines derived from arylal-dehydes. 

D. E. Bergbreiter and M. Newcombe (1983). Alkylation of imine and enamine salts , in Asymmetric Synthesis, Ed. J. D. Morrison. Orlando, Florida Academic Press. Vol. 2A, p. 243 D. Enders (1984). Alkylation of chiral hydrazones , in Asymmetric Synthesis. Ed. J. D. Morrison. Orlando, Florida Academic Press, Vol. 3, p. 275. 

Since the stereochemistry of the newly created quaternary carbon center was apparently determined in the second alkylation process, the core of this method should be applicable to the asymmetric alkylation of aldimine Schiffbase 42 derived from the corresponding a-amino adds. Indeed, di-alanine-, phenylalanine- and leucine-derived imines 42 (R1 = Me, CH2Ph, i-Bu) can be alkylated smoothly under similar conditions, affording the desired non-coded amino acid esters 43 with excellent asymmetric induction, as exemplified in Table 5.7 [19]. 

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