Synthetic studies on bioactive natural products including α,α-disubstituted α-amino acid structure.

最近，含有高度官能化的α-取代的α-氨基酸部分的化合物已被报道具有有趣的生物活性。Lactacystin是从链霉菌（Streptomyces sp.）发酵液中分离得到的一种α-取代的α-氨基酸衍生物，由于其对20 S蛋白酶体的抑制作用，显示出显著的神经营养活性。（R）-2-（羟甲基）谷氨酸是代谢性谷氨酸受体的选择性激动剂。Dysibetaine是从海绵中分离的α-取代的α-氨基酸衍生物。由于该化合物能够诱导小鼠的惊厥行为，因此怀疑其作用于中枢神经系统中的谷氨酸受体。以2-氨基-2-羟甲基丙二醇和苯甲酸为原料合成前手性二醇，在脂肪酶PS存在下，在THF中与乙酸乙烯酯反应，得到单乙酸酯（> 99%ee）。用于评估光学活性乙酸酯作为α-取代α-氨基酸衍生物的潜在手性结构单元。通过Wittig反应、恶唑啉的氢化和水解，该手性结构单元很容易地转化为（R）-2-（羟甲基）谷氨酸和（-）-脱氧甜菜碱的合成中间体。通过Wittig反应、不对称环氧化反应、区域选择性甲基化反应、恶唑啉水解反应和1，2-二醇保护反应，将手性结构单元转化为lactacystin的合成中间体。

Recently, compounds containing highly functionalized a-substituted a-amino acid moieties have been reported to possess intriguing biological activity. Lactacystin is an a-substituted a-amino acid derivative isolated from the culture broth of Streptomyces sp. The compound exhibits significant neurotropic activity due to its ability to inhibit the 20S proteasome. (R)-2-(Hydroxymethyl)glutamic acid is a selective agonist of metabolic glutamate receptor. Dysibetaine is an a-substituted a-amino acid derivative isolated from the marine sponge. As this compound is able to induce convulsive behavior in mice, it was suspected of acting on glutamate receptors in the central nervous system. These biological features have prompted many groups to pursue synthetic studies of compounds containing highly functionalized a-substituted a-amino acid moieties.Prochiral diol prepared from 2-amino-2-hydroxymethylpropane-1,3-diol and benzoic acid, was treated with vinyl acetate in THF in the presence of Lipase PS and gave mono acetate ( >99% ee). For the assessment of optically active acetate as a potential chiral building block of α-substituted α-amino acid derivatives. The chiral building block was easily converted to (R)-2-(hydroxymethyl)glutamic acid and a synthetic intermediate of (-)-deoxydysibetaine by Wittig reaction, hydrogenation and hydrolysis of oxazoline. The chiral building block was easily converted to a synthetic intermediate of lactacystin by Wittig reaction, asymmetric epoxidation, regioselective methylation, hydrolysis of oxazoline and protection of 1,2-diol.