Asymmetric alkylation Schiff base

Tanaka et al.28 have synthesised a series of (S)-chiral Schiff bases as the highly active (yield 69-99%) and enatioselective (ee 50-96%) catalysts in the reaction of addition of dialkylzinc to aldehydes. The stereochemistry of the asymmetric addition was suggested. In a transition state when S-chiral Schiff base was used as chiral source, the alkyl nucleophile attacked Re face of the activated aldehyde and formed the R-configuration alkylated product [13]. 

Stereoselective alkylation with aliphatic bromides and iodides of the Schiff bases of tert-butyl glycinate with (—)-(15,25,55)-2-hydroxypinan-3-one or (+)-(lR,2R,5R)-2-hydroxy-pinan-3-one 150 was reported to produce lipidated amino acids as d- and L-enantiomers in 80 to over 90% ee. 151 Similarly, the asymmetric synthesis of a derivative of arachidonic acid (4) has also been reported. The pure enantiomer was obtained via regioselective functionalization of a chirally pure glutamic acid. 152 ... 

The kinetics of alkylation by benzyl bromide of the Schiff base esters of ammo acids (Ph2C=NCH2CC>2CMe3) in the presence of cinchona salts show features similar to those of enzyme-promoted reactions variable orders, substrate saturation, catalyst inhibition, and non-linear Arrhenius-type plots.125 A tight coordination of the Schiff base substrate by electrostatic interaction with the quaternary N of the cinchona salt provides a favourable chiral environment for asymmetric alkylation. 

The fate of the onium carbanion Q+R incorporated into the organic phase depends on the electrophilic reaction partner. The most studied area in the asymmetric phase-transfer catalysis is that of asymmetric alkylation of active methylene or methine compounds with alkyl halides, in an irreversible manner. The reaction mechanism illustrated above is exemplified by the asymmetric alkylation of glycine Schiff base (Scheme 1.5) [8]. 

In 1989, O Donnell and coworkers successfully utilized cinchona alkaloid-derived chiral quaternary ammonium salts for the asymmetric synthesis of a-amino acids using tert-butyl glycinate benzophenone Schiff base 1 as a key substrate [5]. The asymmetric alkylation of 1 proceeded smoothly under mild phase-transfer... 

In addition to the glycinate Schiff base 1, glycine amide derivatives can be used as prochiral substrates for asymmetric alkylation under phase-transfer conditions. Kumar and Ramachandran examined the benzylation of various Schiff bases of... 

Enantioselective Michael addition of glycine derivatives by means of chiral phase-transfer catalysis has been developed to synthesize various functionalized a-alkyl-a-amino acids. Corey utilized 4d as catalyst for asymmetric Michael addition of glycinate Schiff base 1 to a,(3-unsaturated carbonyl substrates with high enantioselectivity (Scheme 2.15) [35,36]. With methyl acrylate as an acceptor, the a-tert-butyl-y-methyl ester of (S)-glutamic acid can be produced, a functionalized glutamic acid... 

Table 5.5 Asymmetric phase-transfer alkylation of glycine amide Schiff base 22. 

The vast synthetic utility of the asymmetric phase-transfer alkylation of glycine Schiff base 2 has been realized by its successful application to the synthesis of various useful amino acid derivatives and natural products. 

Since the aldimine Schiff base 21 can be readily prepared from glycine, direct stereoselective introduction of two different side chains to 21 by appropriate chiral phase-transfer catalysis would provide an attractive, yet powerful, strategy for the asymmetric synthesis of structurally diverse a,a-dialkyl-a-amino acids. This possibility of a one-pot asymmetric double alkylation has been realized by using N-spiro chiral quaternary ammonium bromide le (Scheme 5.21). 

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. 

The power of this methodology lies in the ability to prepare unnatural amino acid derivatives by asymmetric alkylation of prochiral enolates. Several asymmetric alkylations of the alanine derivative 7, catalysed by the C2-symmetrical quaternary ammonium salt 6d, have been reported these reactions yield unnatural amino acids such as 8 in high enantiomeric excess (Scheme 2) [7]. The chiral salen complex 9 has also been shown to be an effective catalyst for the preparation of a,a-dialkyl a-amino acids [8, 9]. For example, benzylation of the Schiff base 10 gave the a-methyl phenylalanine derivative 11 in 92% ee (Scheme 3) [8]. Similar reactions have been catalysed by the TADDOL 12, and also give a,a-dialkyl a-amino acids in good enantiomeric excess [10]. 

Lygo has extended his asymmetric alkylation methodology to the synthesis of bis-a-amino acids (Scheme 4) [11], Bis-amino acids, such as meso-diaminopirnelic acid, dityrosine and isodityrosine, are found in nature and are thought to act as cross-linking agents which stabilise structural proteins in plants and bacteria. For example, asymmetric alkylation of the Schiff base 3 with the dibromide 13, catalysed by the quaternary ammonium salt le, gave the bis-amino acid derivative 14 in >95% ee. 

In all cases it was reported that the trifluoromethyl group enhances the interaction in the prochiral ion pair, resulting in higher ee. The exception appears to be the asymmetric synthesis of a-amino acids via alkylation of the benzophenone Schiff base of glycine alkyl esters with allyl bromide, which produced a 56% ee with the trifluoromethyl-substituted catalyst compared to 66% with the unsubstituted catalysts TY-benzylcinchoninium chloride (3) or TY-benzylcinchonidinium chloride (4) (eq 5). ... 

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