Racemic and Enantiopure Synthesis and Physicochemical Characterization of the Novel Taste Enhancer N-(1-Carboxyethyl)-6-(hydroxymethyl)pyridinium-3-ol Inner Salt

Abstract

Convenient syntheses were developed to obtain on a multigram scale the novel taste enhancer N-(1-carboxyethyl)-6-(hydroxymethyl)pyridinium-3-ol 1, called alapyridaine, as a racemic mixture and as pure (+)-(S) and (-)-(R) enantiomers, respectively. 5-(Hydroxymethyl)-2-furaldehyde was used as key intermediate and was reacted with l-alanine under alkaline conditions to obtain racemic 1. Alternatively, reductive amination of 5-(hydroxymethyl)-2-furaldehyde with Raney-Ni/hydrogen and l- or d-alanine followed by mild oxidation led to (+)-(S)-1 and (-)-(R)-1, respectively. Racemization was promoted under alkaline and boiling conditions via a carbanion, the formation of which was facilitated by the electron-withdrawing effect of the iminium cation and the resonance-stabilizing capacity of the pyridinium moiety. Under these conditions, 1 was obtained in a 1:1 mixture of the phenol (1) and phenolate (1-H) forms as shown by X-ray diffraction. Racemic 1 formed monoclinic crystals of high molecular organization in which the phenol-type (RS)-1, the phenolate-type (RS)-1-H, sodium cations, and ethanol molecules are present. The crystal structure of [Na(1)(1-H).(C(2)H(6)O)] shows one-dimensional mu(2)-bridging-oxygen polymers stabilized by a three-dimensional network of ionic, hydrogen bond, and pi-stacking interactions with channels occupied by solvent molecules.

Sweet and Umami Taste: Natural Products, Their Chemosensory Targets, and Beyond

“…[77] Although being tasteless on its own, the enantiomer (+)-(S)-alapyridaine was confirmed to significantly decrease the human recognition threshold of umami as well as sweet stimuli, whereas (À)-(R)-alapyridaine was physiologically not active. [78] Additional structure-activity relationship studies revealed that substitution of the alanine moiety in 42 by a glycine moiety converted the sweetness-enhancing alapyridaine into a bitter taste inhibitor. [79] Scheme 1.…”

Systematic studies of structure and physiological activity of alapyridaine. A novel food‐born taste enhancer

“…2) was synthesized and purified as reported recently [20]. Both the enantiomers, (+)-(S)-1 and (-)-(R)-1, were stereospecifically synthesized and purified using food-grade solvents [25]. All alapyridaine samples were essentially free of sodium and chloride.…”

“…This so-called alapyridaine, which was recently found to occur naturally in beef bouillon [23], does not show any taste on its own, but is able to enhance the sweetness of sugars, amino acids, and the artificial sweetener aspartame. While well-known taste enhancers, such as, e. g., monosodium glutamate, guanosine-59-monophosphate or maltol, intensify single taste modalities only, the (+)-(S)-enantiomer of 1 was recently demonstrated to act as a multivalent taste modifier significantly decreasing the human taste thresholds for various sweet, umami, and salty compounds [24,25]. It is, however, yet not known which structural elements are essential for the physiological activity of that molecule.…”

Moleküle und biologische Mechanismen des Süß‐ und Umamigeschmacks

“…[77] Obwohl selbst geschmacklos, stellte sich heraus, dass das Enantiomer (+)-(S)-Alapyridain die menschliche Erkennungsschwelle für umami und süße Reize deutlich herabsetzt, während das (À)-(R)-Alapyridain physiologisch nicht aktiv ist. [78] Zusätzliche Studien zu Struktur-Aktivitäts-Beziehungen (SAR-Studien) zeigten, dass ein Austausch der Alanineinheit in 42 gegen einen Glycinrest das süß verstärkende Alapyridain in einen Bittergeschmack-Inhibitor überführt. [79] Neben der Identifizierung solcher natürlichen Umamigeschmacksverstärker in rohen und verarbeiteten Nahrungsmitteln über den Sensomik-Ansatz konzentrieren sich andere Forschungsansätze auf die thermische Reaktion bekannter, isolierter Nahrungsmittelbestandteile unter küchenüblichen Modellbedingungen, das Screening der zur Geschmacksverstärkung gebildeten Reaktionsprodukte durch sensorische Prüfungen mithilfe menschlicher Testpersonen und die nachfolgende Verifizierung des natürlichen Vorkommens dieser Verbindungen in Nahrungsmitteln durch HPLC-MS/ MS. Zum Beispiel wurde N-Gluconylethanolaminphosphat (43) durch Reaktion von 2-Aminoethyldihydrogenphosphat und d-Gluconolacton erhalten und eine umamiverstärkende Wirkung festgestellt.…”