Concise Synthesis of (2<i>R</i>,4<i>R</i>)-Monatin

Abstract

Monatin, 4-hydroxy-4-(3-indolylmethyl)-glutamic acid, is a naturally occurring sweet amino acid. The (2R,4R)-monatin isomer has been found to be the sweetest among its four stereoisomers. A concise and efficient synthesis of (2R,4R)-monatin was accomplished by the alkylation of (4R)-N-tert-butoxycarbonyl (tBoc)-4-tert-butyldimethylsilyoxy-D-pyroglutamic acid methyl ester with tert-butyl 3-(bromomethyl)-1H-indole-1-carboxylate to give (4R)-N-tBoc-4-tert-butyldimethylsilyloxy-4-(N-tBoc-3-indolylmethyl)-D-pyroglutamic acid methyl ester, i.e., the lactam form of (2R,4R)-monatin with protecting groups. This was followed by the hydrolysis of the lactam ring and deprotection. The 4-hydroxyl D-pyroglutamic acid derivative was demonstrated to be a suitable precursor for the efficient preparation of (2R,4R)-monatin in high optical purity because the alkylation proceeded in regioselective and stereoselective manners at C4 to form appropriate asymmetric tetra-substituted carbon center; the resulting alkylated pyroglutamic acid derivative was then easily converted into the linear form of monatin.

Synthesis of nonracemic hydroxyglutamic acids

“…While the protected methyl (2 S ,4 S )-4-hydroxypyroglutamate formed a basis for the construction of the alkaloid hemerocallisamine skeleton [37], its tert -butyl counterpart was used as a starting material in a multistep synthesis of a functionalized exo -methylenecyclopentane skeleton as an entecavir intermediate [116]. On the other hand, the stereospecific alkylation of methyl (2 R ,4 R )-4-hydroxypyroglutamate was employed in the important approach to (2 R ,4 R )-monatin [117]. Carbapenems can be generated from the intermediary enantiomeric 3-hydroxy- or 4 hydroxy-L-glutamic acids in cell-free environments [118].…”