Glycine, reactions conjugate addition

N-Bis(methylthio)methylene derivatives of amines (iminodithiocarbonates) were first introduced by Hoppe and Beckmann468 for the synthesis of a-amino acids from glycine. The A bis(methylthio)methyleneamines are prepared by reaction of a primary amine with carbon disulfide (HAZARD) in the presence of triethylamine and iodomethane to form a methyl dithiocarbamate derivative, which is then S-alkylated with a second equivalent of iodomethane in the presence of potassium carbonate as the base. Scheme 8,233 illustrates an alternative one pot procedure applied to the synthesis of /erf-butyl N-[bis(methylthio)-methylene]glycinate and its use in diastereoselective conjugate addition under... 

Another relevant pioneering report in this context was carried out by Corey, using cinchona-based chiral ammonium salt 103a as catalyst (Scheme 5.5). In this case, the conjugate addition of tert-butyl glycinate benzophenone imine to cyclohexanone and ethyl vinyl ketone was found to proceed with excellent yields and enantioselectivities and, in the cyclohexanone case, also with almost complete diastereoselectivity. Cesium hydroxide was selected for this particular reaction as the most appropriate base to generate the reactive enolate species. 

Cinchonidine-derived catalyst 173 (10 mol%) has been also employed in the asymmettic synthesis of 4-alkytiden glutamic acid derivatives through a tandem conjugate addition-eUminalion reaction between the Schiff base of glycine tm-butyl ester and activated aUytic acetates under PTC conditions using CsOHH O as base [276]. The reaction, which is performed at -78°C in allows the preparation... 

Numerous guanidine-catalysed asymmetric Michael reactions and its related variants such as aza-Michael, oxa-Michael, phospha-Michael, sulfa-Michael have been reported in the literature. A nonexhaustive selection of conjugate addition reactions that is relevant to green chemistry will be presented. Glycine imines are commonly employed in Michael additions. They are protected a-amino acids and must he deprotected if an amino acid derivative is desired (Scheme 23.5). The large molecular mass of the imine group then makes waste generation a problem. 

A short synthesis of (-f)-monomorine (1562) by Maruoka and coworkers used the chiral phase-transfer catalyst (R)-1672 to mediate an enantioselective conjugate addition between enone 1673 and the imine-protected glycine ester 1674 (Scheme 213). In a remarkable one-pot reaction, the intermediate adduct 1675 was then treated with Hantzsch ester (diethyl 2,6-dimethyl-l,4-dihydropyridine-3,5-dicarboxylate) in mildly acidic medium, which brought about deprotection of the acetal and imine as well as a double reductive amination in which the dihydropyridine acted as the hydrogen transfer agent. The resulting indolizidine ester (—)-1676 was... 

Maruoka and coworkers [65] also reported the total synthesis of (+) mono-morine (127) using a phase-transfer-catalyzed conjugate addition of glycine ester 128 to Michael acceptor 129 as an early key step in the synthesis sequence. Monomorine (127) is a bicyclic amine, known to be the trail pheromone of Monomorium pharanois [66]. The conjugate addition product 131 was subjected to an intramolecular reductive amination and acetal hydrolysis in one pot reaction with Hantzsch ester 132 and trifluoroacetic acid in aqueous... 

Recently, Park and coworkers [112] described an efficient phase-transfer-catalyzed conjugate addition of the glycine imine ester 65a to ethyl 2-(phenylselanyl)acrylate 83. In the presence of catalyst 13b, the adduct 84 was obtained in almost qtxan-titative yield with 96% ee (Scheme 12.10). The potential application of this addition reaction was demonstrated as an important step in the synthesis of (-l-)-polyoxamic acid. 

Note Some protocols do not call for a reduction step. The addition of borohydride at this level may result in disulfide bond cleavage and loss of protein activity in some cases. As an alternative to reduction, add 50pi of 0.2M lysine in 0.5M sodium carbonate, pH 9.5 to each ml of the conjugation reaction to block excess reactive sites. Block for 2 hours at room temperature. Other amine-containing small molecules may be substituted for lysine—such as glycine, Tris buffer, or ethanolamine. 

FIGURE 7.13 Reaction sequence leading to amino acid conjugation, the type of carboxylic acids that are substrates, and the type of amino acids that can conjugate. An example is the addition of glycine to benzoic acid to form hippuric acid. 

Caffeic acid is metabolized by liver enzymes to give ferulic, vanillic acids and their glycine conjugates, which may be excreted into urine. In addition, dihydroferulic acid is produced by catechol o-methyltransferase in the liver. Because of the specificity of this enzyme, only ortho hydroxy-methoxy metabolites may be formed. These reactions may occur in rats as well in humans [15]. Fig. (2) shows the metabolic reactions of caffeic acid in body tissues. 

Michael addition may then take place at the terminus of the conjugated system. Lysine-258 at the active site is alkylated by the suicide inhibitor. The reaction is similar to that of equation 9.7, except that in the Michael addition the pyridoxal ring acts as the electron sink, rather than the N atom originating from the vinyl glycine. 

Additional reactions of glycine include its ability to become conjugated with bile acids to form conjugated bile salts (see Chapter 19), formation of heme (Chapter 7), formation of purine nucleotides (Chapter 10), formation of creatine (see later), and the formation of hippuric acid from benzoic acid. In the last case, an amide linkage is formed between the carboxyl group of benzoic acid and the amino group of glycine. 

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