Imines asymmetric alkylation

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-... 

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.

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]. 

One problem in the anti-selective Michael additions of A-metalated azomethine ylides is ready epimerization after the stereoselective carbon-carbon bond formation. The use of the camphor imines of ot-amino esters should work effectively because camphor is a readily available bulky chiral ketone. With the camphor auxiliary, high asymmetric induction as well as complete inhibition of the undesired epimerization is expected. The lithium enolates derived from the camphor imines of ot-amino esters have been used by McIntosh s group for asymmetric alkylations (106-109). Their Michael additions to some a, p-unsaturated carbonyl compounds have now been examined, but no diastereoselectivity has been observed (108). It is also known that the A-pinanylidene-substituted a-amino esters function as excellent Michael donors in asymmetric Michael additions (110). Lithiation of the camphor... 

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 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. 

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 ... 

The asymmetric addition of organomagnesium and organolithium reagents to a,P-unsaturated carbonyl compounds and especially imines can be achieved in situations where rigid chelation controls the geometry of the transition state. Stereospecific alkyl addition occurs in the case of a chiral leucine-derived imine to provide overall asymmetric alkyl addition to an a,P-unsaturated aldehyde (Scheme 107).380 381... 

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. 

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. 

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]. 

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

A biphenyl and ct-methylnaphthylamine-derived chiral quaternary ammonium salt 23d, which was shown by Lygo to be effective for the asymmetric alkylation of Schiffs base 20, was also effective in the Michael reaction (Scheme 7.12) [43]. Notably, the enantioselectivity was highly dependent on the reaction conditions and substrates used. The Michael reaction of imine esters such as benzhydryl and benzyl esters with a,p-unsaturated ketones under solid-liquid phase-transfer catalysis conditions afforded the Michael adduct in up to 94% ee and 91% ee, respectively, while the tert-butyl ester showed moderate enantioselectivity (Scheme 7.12). Interestingly, in contrast to earlier reports, acrylate [42] and acrylamides failed to undergo the Michael reaction under these optimized conditions. 

Metal-based asymmetric phase-transfer catalysts have mainly been used to catalyze two carbon-carbon bond-forming reactions (1) the asymmetric alkylation of amino acid-derived enolates and (2) Darzens condensations [5]. The alkylation ofprochiral glycine or alanine derivatives [3] is a popular and successful strategy for the preparation of acyclic a-amino acids and a-methyl-a-amino acids respectively (Scheme 8.1). In order to facilitate the generation of these enolates and to protect the amine substituent, an imine moiety is used to increase the acidity of the a-hydrogens, and therefore allow the use of relatively mild bases (such as metal hydroxides) to achieve the alkylation. In the case of a prochiral glycine-derived imine (Scheme 8.1 R3 = H), if monoalkylation is desired, the new chiral methine group... 

Acyclic /V-alkylimines, asymmetric hydrogenation, 10, 56 Acyclic ( j3-allyl)cobalt complexes, oxidation reactions, 7, 58 Acyclic allylic esters, alkylation, 11, 76 Acyclic aromatic imines, asymmetric hydrogenation, 10, 56 Acyclic 1-buly l-( )5-pencadienyl) iron cations, preparation and reactivity, 6, 156... 

The asymmetric alkylation of cyclic ketones, imines of glycine esters, and achiral, enolizable carbonyl compounds in the presence of chiral phase-transfer organoca-talysts is an efficient method for the preparation of a broad variety of interesting compounds in the optically active form. The reactions are not only highly efficient, as has been shown impressively by, e.g., the synthesis of enantiomerically pure a-amino acids, but also employ readily available and inexpensive catalysts. This makes enantioselective alkylation via chiral phase-transfer catalysts attractive for large-scale applications also. A broad range of highly efficient chiral phase-transfer catalysts is also available. 

Lygo, B. and Andrews, B.I. (2004) Asymmetric phase-transfer catalysis utilizing chiral quaternary ammonium salts asymmetric alkylation of glycine imines. Ace. Chem. Res., 37, 518. 

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

Asymmetric synthesis of ketones (7, 17). Meyers and Williams have extended the asymmetric alkylation of cyclohexanones via the imines formed from 1 to acyclic ketones. Initially optical yields were only 3-44%, but they can be increased to 20-98% by heating the lithioenamines to reflux (THF) prior to alkylation at -78°. Evidently the lithioenamines formed at —20° are mixtures of (E)- and (Z)-isomers. The optical yields are lowered as the size of substituents on the ketone increases. Example ... 

Asymmetric Alkylations. The use of nitrogen derivatives of carbonyl compounds (imines, imides, amides, sultams, oxazo-lines) is often the most efficient procedure for achieving a-alkylations. Chiral auxiliaries bearing heteroatoms in a 1,2-relationship appear to work best, as they have chelation sites for the metal cation. High levels of asymmetric induction can thus be achieved due to the system rigidity. Cyclic ketones have been alkylated via the lithiated enamine formed from L-f-leucine f-butyl ester (eq 1). High enantiomeric excesses and predictability of absolute configuration make this method attractive. 

Activation of C=N double bonds by copper Lewis acids for nucleophilic addition has also been reported (Sch. 37) [73]. The a-imino ester 157 undergoes alkylation at the imine carbon with a variety of nucleophiles when catalyzed by copper Lewis acids. The presence of the electron-withdrawing ester group increases the reactivity of the imine and also assists in the formation of a stable five-membered chelate with the Lewis acid. Evidence for Cu(I) Lewis-acid catalysis and a tetrahedral chelate was obtained by FTIR spectroscopy, from the crystal structure of the catalyst, and from several control experiments. The authors rule out the intermediacy of a copper enol-ate in these transformations. The asymmetric alkylation of A,0-acetals with enol silanes mediated by a copper Lewis acid proceeding with high selectivity has been reported [74],... 

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