Amino acids, phase-transfer catalyzed syntheses

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). 

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. 

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-... 

The synthesis of the chiral copper catalyst is very easy to reproduce. The complex catalyses the asymmetric alkylation of enolates of a range of amino acids, thus allowing the synthesis of enantiomeric ally enriched a,a disubstituted amino acids with up to 92% ee. The procedure combines the synthetic simplicity of the Phase Transfer Catalyst (PTC) approach, with the advantages of catalysis by metal complexes. The chemistry is compatible with the use of methyl ester substrates, thus avoiding the use of iso-propyl or ferf-butyl esters which are needed for cinchona-alkaloid catalyzed reactions[4], where the steric bulk of the ester is important for efficient asymmetric induction. Another advantage compared with cinchona-alkaloid systems is that copper(II)(chsalen) catalyses the alkylation of substrates derived from a range of amino acids, not just glycine and alanine (Table 2.4). 

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... 

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. 

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. 

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. 

The asymmetric synthesis of a-alkyl-a-amino acids using a chiral catalyst is a useful method for the preparation of both natural and unnatural amino acids. O Donnell et al. developed the cinchona alkaloid-catalyzed alkylation of glycine derivatives [49]. However, almost all of the chiral phase-transfer catalysts were restricted to cinchona alkaloid derivatives. In 1999, Maruoka and co-workers designed a chiral ammonium salt bearing a binaphthyl backbone as a chiral phase-transfer catalyst (10a) (Figure 10.11), and demonstrated its catalytic activity... 

Liberation of amines. A modification of the classical Gabriel synthesis to gain access to a-amino acids using chiral a-bromoalkanoic esters to react with potassium phthalimide catalyzed by a chiral phase transfer agent has been reported. Unfortunately, the results are not very satisfactory. 

The elongation phase of polypeptide synthesis is depicted in Fig. 9-12. The 508 subunit is a peptidyl transferase that catalyzes the formation of a peptide bond between amino acids. The 238 rRNA is responsible for this catalytic activity. As its name implies, it transfers the fMet (and in later reactions a peptide) from the tRNA that occnpies the P site to the amino acid on the tRNA in the A site. To do this, the amino group of... 

Liquid-liquid-solid reactors are commonly used for biphasic reactions catalyzed by immobilized phase-transfer catalysts (which form the third, solid phase). Certain basic aspects of such reactors were considered in Chapter 19. Three-phase reactions of this type are also encountered in biological reactions, for example, the enzymatic synthesis of amino acid esters in polyphasic media (Vidaluc et al., 1983), and the production of L-phenylalanine utilizing enzymatic resolution in the presence of an organic solvent (Dahod and Empie, 1986). Predictably, the performance of these reactors is influenced by the usual kinetic and mass transfer aspects of heterogeneous systems (see Lilly, 1982 Chen et al., 1982 Woodley et al., 1991a,b). Additionally, performance is also influenced by the complex hydrodynamics associated with the flow of two liquids past a bed of solids (Mitarai and Kawakami, 1994 Huneke and Flaschel, 1998). It is noteworthy, for instance, that phase distribution within the reactor is different from that in the feed and is also a function of position within the reactor and within the voids of each pellet in the bed. More intensive research is needed before these reactors can be rationally designed. 

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