A Simple Cycloaddition Approach to a Racemate of the Natural Sweetener Monatin

Holzapfel, Cedric W.; Bischofberger, Karl; Olivier, Johan

doi:10.1080/00397919408010241

Cited by 20 publications

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“…Various methods have been reported regarding the synthesis of monatin, some of which produce a mixture of stereoisomers, [2][3][4][5] while others describe stereoselective syntheses. [6][7][8][9][10][11] However, there have been no reports wherein all four stereoisomers having the same structural formula as 1a are synthesized, isolated, and characterized as pure substances.…”

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Preparation and Characterization of Four Stereoisomers of Monatin

et al. 2016

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Monatin is a naturally occurring, sweet amino acid comprising four stereoisomers due to its two asymmetric centers at C2 and C4. However, the characteristics of each stereoisomer have not yet been fully investigated. To obtain a sufficient amount of racemic monatin for optical resolution, a synthetic method was developed by modifying a possible biosynthetic pathway, i.e., a cross-aldol reaction and subsequent transamination. The key intermediate, 4-hydroxy-4-(3-indolylmethyl)-2-ketoglutaric acid, was obtained via the crossaldol reaction of pyruvic acid and indole-3-pyruvic acid. Subsequently, the carbonyl group was converted to a hydroxyimino group through reaction with hydroxylamine and then to an amino group via hydrogenation to produce monatin. Next, the racemic monatin was divided into mixtures of two pairs of enantiomers through recrystallization. Finally, both enantiomers of the N-carbobenzoxy-γ-lactone derivatives of monatin were separated by preparative HPLC and deprotected. It was found that all optically pure stereoisomers exhibited a sweet taste. The isomer that displayed the most intense sweetness was the (2R,4R)-isomer, as determined by single crystal X-ray structure analysis of the monatin potassium salt, whereas the least sweet isomer was the (2S,4S)-isomer, which demonstrated a far lower sweetness than was previously reported.

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Preparation and Characterization of Four Stereoisomers of Monatin

et al. 2016

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“…3C). IEA and racemic IAA were synthesized from indole and methyl 2-(bromomethyl)acrylate (1) following a procedure from Holzapfel et al (27). Methyl 2-(bromomethyl) acrylate was obtained in two steps from methyl acrylate and paraformaldehyde, followed by bromination with PBr 3 (28,29).…”

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Biosynthesis of Violacein, Structure and Function of l-Tryptophan Oxidase VioA from Chromobacterium violaceum

Füller

Röpke

Krausze

et al. 2016

Journal of Biological Chemistry

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Violacein is a natural purple pigment of Chromobacterium violaceum with potential medical applications as antimicrobial, antiviral, and anticancer drugs. The initial step of violacein biosynthesis is the oxidative conversion of L-tryptophan into the corresponding ␣-imine catalyzed by the flavoenzyme L-tryptophan oxidase (VioA). A substrate-related (3-(1H-indol-3-yl)-2-methylpropanoic acid) and a product-related (2-(1H-indol-3-ylmethyl)prop-2-enoic acid) competitive VioA inhibitor was synthesized for subsequent kinetic and x-ray crystallographic investigations. Structures of the binary VioA⅐FADH 2 and of the ternary VioA⅐FADH 2 ⅐2-(1H-indol-3-ylmethyl)prop-2-enoic acid complex were resolved. VioA forms a "loosely associated" homodimer as indicated by small-angle x-ray scattering experiments. VioA belongs to the glutathione reductase family 2 of The amino acid tryptophan (Trp) is a versatile metabolite that is shunted into several microbial secondary pathways. The oxidative dimerization of two Trp scaffolds is an essential step for the synthesis of the natural bisindole compounds violacein, rebeccamycin, and staurosporine. The water-insoluble purple pigment violacein is mainly produced by the bacteria Chromobacterium violaceum and Janthinobacterium lividum in tropical habitats where it might be responsible for the shielding against UV radiation (1-3). Various biological activities of violacein, including antibacterial, antiviral, as well as cytotoxic effects against several tumor cell lines, have been demonstrated (4). The related compounds rebeccamycin and staurosporine show strong antitumorigenic activity because of DNA topoisomerase or protein kinase inhibition (5, 6).Synthesis of violacein, rebeccamycin, or staurosporine is based on a closely related initial pathway in which orthologous enzymes catalyze the oxidation of a Trp moiety into the related indole-3-pyruvic acid (IPA) 2 imine by the enzymes VioA, RebO, or StaO ( Fig. 1) (7-9). Subsequently, oxidative coupling of two imines by VioB, RebD, or StaD results in the formation of a short-lived compound that was proposed to be an IPA imine dimer (7, 10). For the synthesis of rebeccamycin and staurosporine, this reactive intermediate is spontaneously converted into chromopyrrolic acid (11-13). By contrast, violacein biosynthesis requires a key intramolecular rearrangement. The postulated IPA imine dimer is the substrate of VioE, which is catalyzing a [1,2]-shift of the indole ring to produce protodeoxyviolaceinic acid (7,14). Fig. 1 gives a schematic overview about the related pathways as follows: common enzymatic reactions and the involved cofactors are highlighted (gray shading), subsequent steps for the synthesis of violacein (VioE, VioD, VioC, and one autocatalytic step) (3, 7), rebeccamycin (RebP, RebC, RebG, and RebM) (15, 16), and staurosporine (StaP, StaC, StaG, StaN, StaMA, and StaMB) (16) are indicated.Synthesis of violacein starts with the FAD-dependent oxidation of L-Trp to IPA imine catalyzed by VioA. The VioA protein from C. violaceum shares a su...

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“…The racemic isoxazoline diester 4 was obtained2 from the 1,3‐dipolar cycloaddition of 2 with the nitrile oxide generated in situ from the chlorooxime 3 . The introduction of the first stereogenic centre was achieved by a chemoenzymatic step.…”

Section: Resultsmentioning

confidence: 99%

“…Some synthetic approaches to racemic monatin have been described in the open or patent literature 2,3. Moreover, some stereoselective syntheses of (–)‐monatin have also been reported 4–6.…”

Section: Introductionmentioning

confidence: 99%

Monatin and Its Stereoisomers: Chemoenzymatic Synthesis and Taste Properties

et al. 2005

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The sweet natural compound monatin 1 has two stereogenic centres and the (2S,4S) absolute configuration has been attributed to the natural isomer. We obtained all four stereoisomers as pure compounds by a six-step synthetic sequence. The stereogenic centre at C-4 was introduced stereoselectively by a regio-and enantiospecific enzymatic hydrolysis of the racemic ethyl dicarboxylate 4 using a protease from Aspergillus oryzae. The absolute configuration of the intermediate products was assigned by X-ray diffraction of chiral derivatives. The stereogenic centre at C-2 was introduced non-specifically, and the resulting diastereomeric mixtures were separated by RP-HPLC. The absolute configurations of the final products were established by comparing retention

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A Simple Cycloaddition Approach to a Racemate of the Natural Sweetener Monatin

Cited by 20 publications

References 4 publications

Preparation and Characterization of Four Stereoisomers of Monatin

Preparation and Characterization of Four Stereoisomers of Monatin

Biosynthesis of Violacein, Structure and Function of l-Tryptophan Oxidase VioA from Chromobacterium violaceum

Monatin and Its Stereoisomers: Chemoenzymatic Synthesis and Taste Properties

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