Amino Yusuke, Nishi Seiichi, Izawa Kunisuke
Institute for Innovation, Ajinomoto Co., Inc.
Chem Pharm Bull (Tokyo). 2017;65(9):854-861. doi: 10.1248/cpb.c17-00391.
Teneraic acid (piperidine-2,6-dicarboxylic acid) is a naturally occurring imino acid that comprises three stereoisomers due to its two asymmetric centers at C2 and C6. The configuration of natural teneraic acid is reported to correspond to trans-(2S,6S). However, a few studies are focused on the stereospecific synthesis of trans-(2S,6S)-teneraic acid. The present study investigates a convenient synthetic method that includes regiospecific anodic oxidation and stereospecific cobalt-catalyzed carbonylation to obtain trans-(2S,6S)-teneraic acid. Methyl (S)-N-benzoyl-α-methoxypipecolate, the key intermediate that displays a structure that corresponds to an intermediate (N-α-hydroxyalkyl amide) of intramolecular amidocarbonylation, was obtained via an anodic oxidation of methyl (S)-N-benzoylpipecolate. Subsequently, cobalt-catalyzed carbonylation converted the methyl (S)-N-benzoyl-α-methoxypipecolate to trans-(2S,6S)-N-benzoyl-teneraic acid dimethyl ester in good optical purity (>95% enantiomeric excess (ee)) and modest yield (63%). Finally, de-protection occurred via acidic hydrolysis to obtain trans-(2S,6S)-teneraic acid. The stereochemistry of synthesized teneraic acid was confirmed as corresponding to trans-(2S,6S) by comparing its physical properties with those of a cis-meso-isomer and those of a trans-(2S,6S)-isomer that were reported in previous studies.
特内二酸（哌啶 -2,6 -二羧酸）是一种天然存在的亚氨基酸，由于其在C2和C6处有两个不对称中心，故包含三种立体异构体。据报道，天然特内二酸的构型对应于反式 -（2S,6S）。然而，少数研究聚焦于反式 -（2S,6S）-特内二酸的立体特异性合成。本研究探索了一种简便的合成方法，该方法包括区域特异性阳极氧化和立体特异性钴催化羰基化反应，以获得反式 -（2S,6S）-特内二酸。（S）-N -苯甲酰基-α -甲氧基哌啶甲酯是关键中间体，其结构与分子内酰胺羰基化反应的中间体（N -α -羟烷基酰胺）相对应，通过（S）-N -苯甲酰基哌啶甲酯的阳极氧化反应获得。随后，钴催化羰基化反应将（S）-N -苯甲酰基-α -甲氧基哌啶甲酯转化为具有良好光学纯度（对映体过量（ee）>95%）和适度产率（63%）的反式 -（2S,6S）-N -苯甲酰基 -特内二酸二甲酯。最后，通过酸性水解进行脱保护，得到反式 -（2S,6S）-特内二酸。通过将合成的特内二酸的物理性质与先前研究中报道的顺式 -内消旋异构体和反式 -（2S,6S）-异构体的物理性质进行比较，确认了合成的特内二酸的立体化学对应于反式 -（2S,6S）。
