Amino Yusuke
Institute for Innovation, Ajinomoto Co., Inc.
Chem Pharm Bull (Tokyo). 2016;64(8):1242-7. doi: 10.1248/cpb.c16-00358.
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.
莫那甜，即4-羟基-4-(3-吲哚甲基)-谷氨酸，是一种天然存在的甜味氨基酸。已发现(2R,4R)-莫那甜异构体在其四种立体异构体中甜度最高。通过将(4R)-N-叔丁氧羰基（tBoc）-4-叔丁基二甲基硅氧基-D-焦谷氨酸甲酯与叔丁基3-(溴甲基)-1H-吲哚-1-羧酸酯进行烷基化反应，得到(4R)-N-tBoc-4-叔丁基二甲基硅氧基-4-(N-tBoc-3-吲哚甲基)-D-焦谷氨酸甲酯，即带有保护基的(2R,4R)-莫那甜的内酰胺形式。随后对内酰胺环进行水解并脱保护。4-羟基-D-焦谷氨酸衍生物被证明是高效制备高光学纯度(2R,4R)-莫那甜的合适前体，因为烷基化反应在C4处以区域选择性和立体选择性方式进行，形成合适的不对称四取代碳中心；然后将所得的烷基化焦谷氨酸衍生物轻松转化为莫那甜的线性形式。
