Glycine monoalkylation

Scheme 17 illustrates enantioselective synthesis of a-amino acids by phase-transfer-catalyzed alkylation (46). Reaction of a protected glycine derivative and between 1.2 and 5 equiv of a reactive organic halide in a 50% aqueous sodium hydroxide-dichloromethane mixture containing 1-benzylcinchoninium chloride (BCNC) as catalyst gives the optically active alkylation product. Only monoalkylated products are obtained. Allylic, benzylic, methyl, and primary halides can be used as alkylating agents. Similarly, optically active a-methyl amino acid derivatives can be prepared by this method in up to 50% ee. 

Monoalkylation of Schiff Bases Derived from Glycine... 

Asymmetric Monoalkylation of Glycine Ester Schiff Bases... 

The requisite aldimine Schiff base 21 can be readily prepared by the simple imine formation between glycine tert-butyl ester and p-chlorobenzaldehyde in MeOH at room temperature, with the aid of MgS04. The asymmetric monoalkylation of 21 was... 

Chiral salen-Cu(II) complex 39c also promoted selective monoalkylation of glycine derivative 20 to produce the corresponding a-amino acids (R)-42 with enantiomeric excesses in the range of 70 to 80% (Scheme 7.10) [32], The enantiomeric excess was... 

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... 

In 1978, O Donnell and coworkers developed the benzophenone imines of glycine alkyl esters 4 as glycine anion equivalents, which have been found to be perfed to use in the phase-transfer catalysis [10]. An essential feature of this reaction system lies in the selective mono substitution of the starting Schiff base, the O Donnell substrate 4. This can be possible because of the significant difference in acidity of a-hydrogen between starting substrate 4 p/C,(DMSO) 18.7 (R=Et)] and a-monosubstituted produd S p/C,(DMSO) 22.8 (R=Et, E = Me), 23.2 (R=Et, E = CH2Ph)] [11]. This dramatic acidity difference makes it possible for selective formation of only monoalkylated product without concomitant production of undesired dialkylated produd or racemization. 

Ooi and Maruoka developed an efficient phase transfer catalyst (46a-e), which consisted of chiral N-spiro ammonium salts with binaphthalene skeleton. 3,3 -(3,4,5-Trifluorophenyl)ammonium salt (46e) provided a perfect stereoselection in benzylation of benzophenone Schiffbase of glycine terf-butyl ester (47) (Scheme 5.13, Table 5.5) [19]. The perfect stereoselective alkylation is applicable for a variety of alkyl bromides in the presence of 1 mol% of the catalyst (46e). Not only monoalkylation but also the consecutive double alkylation of 49 was successful to give 50 in excellent enantioselectivities (Scheme 5.14) [20]. The protocol is useful for the enantioselective aldol reaction of 47 with aldehyde (51) [21] and a-imino ester [22], in which catalysts (46f) and (46g) were effective (Scheme 5.15) [23]. 

O Donnell reported the asymmetric alkylation of the Schiff base of tert-h xty glycinate using TV-benzylcinchonium chloride (Scheme 3.26b, [151]). This process, which works for methyl, primary alkyl, allyl, and benzyl halides (Table 3.11), is noteworthy because the substrate is acyclic and because monoalkylation is achieved without racemization under the reaction conditions. The observed chirality sense may be rationalized by assuming an jE fO)-enolate and Jt-stacking of the benzophenone rings of the enolate above the quinoline ring on the catalyst, and approach of the electrophile as before. 

The reaction usually does not stop with monoalkylation, but instead continues via nucleophilic attack of the monoalkylated amino acid on another molecule of alkylator. This can ultimately give rise to the quaternary ammonium salt of the amino acid, also referred to as the betaine of the amino acid. Hence, monomethylation of glycine produces sarcosine, a molecule that is involved in the metabolism of muscle, while trimethylation produces... 

Some alternative but related methods for the homologation of glycine have also been developed. Bis(diphenylphosphino)glycine methyl ester yields an enolate (189), when treated with potassium t-butoxide, which can be cleanly monoalkyl-ated with, for example, benzyl bromide. The phosphorus group is removed by acid hydrolysis. The oxazolin-5-ones (190), derived from A/ benzoyl-a-amino-acids and acetic anhydride, can be readily alkylated in the 4-position hydrolysis gives a,a-disubstituted JV-benzoyl-a-amino-acids. ... 

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