Amino acids, phase-transfer catalyzed

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. 

The phase-transfer-catalyzed enantioselective direct aldol reactions of glycine donor with aldehyde acceptors provide an ideal method for the simultaneous construction of the primary structure and stereochemical integrity of P-hydroxy-a-amino acids, which are extremely important chiral units. In the first report from the Miller s group, N-benzyldnchorudinium chloride (4a) was employed as a catalyst for the reaction of 1 with heptanal, and the corresponding aldol product 21 was obtained in 74% yield, though the diastereo- and enantioselectivities were unfortunately not satisfactory (Scheme 2.18) [40]. 

Access to enantioenriched carbonyl compounds of high value which possess quaternary a-carbon stereocenters containing hetero-functionalities represents one of the most challenging tasks in phase-transfer-catalyzed asymmetric alkylation. In due course, Maruoka and coworkers devised the asymmetric alkylation of cyclic a-amino-P-keto esters 67 with C2-symmetric phase-transfer catalyst lh as a means of obtaining aza-cyclic amino acids with quaternary stereocenters (Scheme 5.32) [33]. 

Further great advances in the field of asymmetric alkylation reactions have been made by several groups working on chiral phase-transfer-catalyzed alkylation of glycinates (see also Section 3.1). A pioneer in this field is the O Donnell group [53, 54] who developed the first a-amino acid ester synthesis using this methodol-... 

Table 4.5 Phase-transfer-catalyzed enantioselective benzylation of aldimine Schiff bases derived from a-alkyl-a-amino acids.3) (For experimental details see Chapter 14.15.1).

Most applications of this derivative have been for the preparation and modihcation of amino acids, although some applications in the area of carbohydrates have been reported. The derivative is stable to -butyllithium, lithium diisopropylamide, and f-BuOK. Various substituted benzylidenes have been used for amine protection of amino acids during phase transfer catalyzed alkylations. 

The enantioselective phase-transfer catalyzed Michael addition of A-(diphenyl-methylene)glycine fert-butyl ester to several Michael acceptors such as methyl acrylate, cyclohex-2-enone and ethyl vinyl ketone was initially studied by Corey et al. employing 0(9)-aUyl-Af-9-anlhraceny]melhylcinchonidimum bromide (173) (Fig. 2.24) as catalyst and cesium hydroxide as base [272]. Different studies followed this pioneering woik, presenting diverse modifications over the standard procedure such as the employment of non-ionic bases [273], variations of the nucleophile functionality [274], and using new chiral phase-transfer catalysts, the most attention paid to this latter feature. For instance, catalyst 173 was successfully employed in the enantioselective synthesis of any of the isotopomers of different natural and unnatural amino acids... 

Scheme 85 Phase-transfer catalyzed syntheses of (non-) natural amino acids starting fiom the achiral glycine Schiffhase 374...

Phase Transfer Catalyzed Alkylation (GlaxoSmithKline). The phase transfer catalyzed synthesis of unnatural amino acid precursors was accomplished on a kilogram scale with medium ee values, which were upgraded by crystallization of the product to more than 99%. Decisive was the addition of the base in a last step to avoid decomposition of the cinchonidinium catalyst via elimination (91). 

Ooi T, Takeuchi M, Kato D, Uematsu Y, Tayama E, Sakai D, Maruoka K. Highly enantioselective phase-transfer-catalyzed alkylation of protected a-amino acid amides toward practical asymmetric synthesis of vicinal diamines, a-amino ketones, and a-amino alcohols. J. Am. Chem. Soc. 2005 127(14) 5073-5083. 

Another route to the racemic amino acid amides is also depicted in Scheme 6, i.e., phase transfer-catalyzed alkylation of the benzaldehyde Schiff bases of amino acid amides (16) gives access to the desired substrates [46]. Especially alkylation with activated alkyl bromides like allylic or benzylic bromides results in high yields of the disubstituted amino acid amides. 

We prepared the (5)-enantiomer of cericlamine via enzymatic resolution of a-methyl-3,4-dichlorophenylalanine amide (28) and subsequent reduction of the amino acid as described in Scheme 11 [61]. Racemic a-methyl-3,4-dichlorophenylalanine amide (28) is prepared by phase transfer-catalyzed benzylation of the benzaldehyde Schiff base of alanine amide (27) followed by acidic workup. Since this substrate is nearly insoluble in water, the enzymatic resolution using the amidase from O. anthropi NCIMB 40321 is performed at pH 5.3. At this pH there is a sufficient amount of the substrate in solution and still approximately 50% of the amidase activity left to allow the enzymatic hydrolysis... 

Synthesis of the peptide bond takes place in the next step. Ribosomal peptidyl-transferase catalyzes (without consumption of ATP or GTP) the transfer of the peptide chain from the tRNA at the P site to the NH2 group of the amino acid residue of the tRNA at the A site. The ribosome s peptidyltransferase activity is not located in one of the ribosomal proteins, but in the 28 S rRNA. Catalytically active RNAs of this type are known as ribo-zymes (cf. p. 246). It is thought that the few surviving ribozymes are remnants of the RNA world"—an early phase of evolution in which proteins were not as important as they are today. 

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... 

A major breakthrough in the use of Nobin as an asymmetric phase-transfer catalyst came when Belokon and coworkers applied it to the alkylation of glycine-derived nickel(II) complex 11a under the conditions shown in Scheme 8.13 [25], Representative results are given in Table 8.1, which illustrate that benzylic and allylic halides react very rapidly and highly enantioselectively to produce a-amino acids. Intrigu-ingly, in this case (R)-Nobin catalyzes the formation of (R)-amino acids, which is the opposite enantioselectivity to that observed for the alkylation of alanine derivative 16b [21,24],... 

The very short reaction times required for the alkylation of substrate 11a with benzylic bromides using Nobin as an asymmetric phase-transfer catalyst are important for the synthesis of 18F-fluorinated amino adds for use in positron-emission tomography (PET)-imaging studies. Thus, Krasikova and Belokon have developed a synthesis of 2-[18F]fluoro-L-tyrosine and 6-[18F]fluoro-L-Dopa employing a (S)-Nobin-catalyzed asymmetric alkylation of glycine derivative 11a as the key step, as shown in Scheme 8.14 [29]. The entire synthesis (induding semi-preparative HPLC purification) could be completed in 110 to 120 min, which corresponds to one half-life of18 F. Both the chemical and enantiomeric purity of the final amino acids were found to be suitable for clinical use. 

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