Pyridylalanines

Schafer, S., Saunders, L., Schhmme, S., Valkov, V, Wagner, J., Kratz, F. et al. (2009) Pyridylalanine-containing hydroxamic adds as selective HDAC6 inhihitors. ChemMedChem, 4, 283—290. 

Musso et al. (87,97) have developed an elegant synthesis of muscaflavin dimethyl ester (61) (Scheme 8). It is conceptionally similar to the synthesis of decarboxybetalains described before. The synthesis starts with conversion of pyridylalanine derivative 86 to the dimethyl ester 87 by esterification and consecutive N-protection with the base-labile p-toluenesulfonylethoxycarbonyl group. For cleavage of the pyridine ring, 87 was transformed into the A -methoxy-pyridinium salt (88) which was then reacted with pyrrolidine in tetrahydrofuran... 

Access to peptide mimetics and enzyme inhibitors was accomplished by the construction of pyridylalanine derivatives [139], Once incorporated into peptides, the resultant structure was capable of coordinating to cations. The desired amino acid 397 was prepared from 396 by a Heck reaction using an acrylic acid ester followed by hydrogenolysis. This species could then be incorporated into the desired mimetic system 398 that was capable of complexation with europium ions. 

The properties of the N-acyl amino acid derivative and the amino acid itself can be important if crystallization is employed to ensure high optical purity. However, in the experience of the authors, it is seldom a problem. Only 3-pyridylalanine could not be purified to high optical purity by recrystallization. Use of enzymes to enhance enantiomeric excess as well as allowing the use of mild hydrolysis conditions has been advocated by others [12]. Amino acids are surprisingly stable to acid-induced racemization. 

Schafer S et al (2009) Pyridylalanine-containing hydroxamic acids as selective HDAC6 inhibitors. ChemMedChem 4(2) 283-290... 

At almost the same time. Miller et al. published a communication on pyridylalanine (Pal)-peptide 45 catalyzed enantioselective allenoate additions to A-acylimines 46 with moderate to good yields with high enantioselectivities (Scheme 1.21)." ... 

The preparation of 4-(3-pyridylmethyl)oxazolidine-2,5-dione 1194, the NCA of j8-pyridylalanine, is made difficult by the presence of a pyridyl group in the amino acid. The pyridyl group complicated attempts to phosgenate the amino acid, since hydrogen chloride generated in the phosgenation reaction formed insoluble salts with the amino acid and with any anhydride that may have formed [877]. 

L-Omithiiie C13) L-HomopheylaJanine (CM) UTireonine (CIS) 1 3-Pyridylalanine (C16) D-Histidine (C17) LUucine(C18)... 

A closely related transformation was reported by the group of Miller, who used 3-pyridylalanine (Pal) based catalysts for the enantioselective addition of aUenoates... 

Miller and coworkers have performed kinetic studies on a pyridylalanine-peptide catalyzed enantioselective coupling of allenoates 16 and N-acyl imines 17 to investigate the mechanism of the aza-MBH reaction [20]. In the catalytic cycle of a typical MBH/aza-MBH reaction, the proton transfer step or C-C bond formation is often considered as the rate-determining step. However, through mechanistic... 

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