Structure elucidation of and synthetic approaches to monatin, a metabolite from Schlerochiton ilicifolius

[摘要] ENGLISH ABSTRACT:Monatin, or 4-hydroxy-4-(3-indolylmethyl) glutamic acid is a high-intensity sweet tastingamino acid found in the root bark of the indigenous plant Schlerochiton ilicifolius. In thethesis the isolation, structure elucidation and a number of synthetic approaches towardthe total synthesis of monatin are described.Extensive fractionation of an aqueous extract of the root bark of S. ilicifolius usingAG50WX8 strong acid cation exchange resin followed by successive gel filtrationprocedures using Biogel P2- and Sephadex G10 gels and guided by the intense sweettaste resulted in the isolation of monatin as a mixture of salts in which the sodium saltpredominates. Potassium and calcium are the two other cations present.The structure elucidation is based mainly on the analysis of data obtained for monatinand the lactone ester of the N-2,4-dinitrophenyl derivative, prepared by reaction ofmonatin with Sangers reagent and diazomethane, by 1H and 13C n.m.r. techniques. TheX-ray crystallographic study of both monatin and the derivative proved disappointing inthat the reflections measured were weak and as a consequence refinement of the datawas severely curtailed. However the resultant structures do show the skeletal atoms ofthe two compounds and in each case the relative stereochemistry of the two chiralcentres could be deduced. A comparison of the specific rotation of monatin with thoseof related 4-hydroxy-4-methylglutamic acids indicates that monatin could have the(2S,4S) configuration.Retrosynthetic analysis of the monatin molecule identified a number of routes whichcould be utilized for the synthesis of monatin and analogues in which the indole moiety isreplaced by a phenyl or aryl group. Seven approaches toward the synthesis of monatinwere investigated using in most instances model compounds to establish optimumreaction conditions. Only the last approach, based on a 1,3-dipolar cyclo-additionreaction met with a measure of success: reaction of the 1,3-dipolar compound formed byreaction of N-t-Boc-indole-3-aldehyde with methyl N-benzylglycinate, with thedipolarophile methyl 2-acetoxyacrylate, generated a pyrrolidine with the requisitesubstituents needed for the monatin structure. In the event the final step, the cleavage ofthe C-2--N bond of the substituted pyrrolidine ring to give monatin, failed.During the investigation of the 1,3-dipolar cycloaddition reaction several substitutedpyrrolidines were prepared. In each case several racemic stereoisomers were formed. Inaddition a number of substituted oxazolines and pyrrolizidines were obtained as minorby-products during these reactions. The stereochemistry of these compounds wasdeduced from the proton-proton nuclear Overhauser effect studies and X-raycrystallographic data.

[发布机构] Stellenbosch University