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-氨基酸的化合物被报道具有有趣的生物活性。乳酸菌素是从链霉菌发酵液中分离得到的α-取代α-氨基酸衍生物。由于其抑制20S蛋白酶体的能力，该化合物显示出显著的神经亲和性。(R)-2-羟甲基谷氨酸是代谢性谷氨酸受体的选择性激动剂。二西甜菜碱是从海绵中分离得到的一种a-取代的a-氨基酸衍生物。由于这种化合物能够诱导小鼠的惊厥行为，因此它被怀疑作用于中枢神经系统中的谷氨酸受体。这些生物学特性促使许多研究小组致力于合成含有高度功能化的α-取代a-氨基酸基团的化合物。由2-氨基-2-羟甲基丙烷-1，3-二醇和苯甲酸制备的前手性二醇在脂肪酶PS的存在下与乙酸乙烯酯在四氢呋喃中反应，得到单乙酸酯(&gt；99%ee)。用于评估光学活性醋酸酯作为潜在的α取代的α-氨基酸衍生物的手性构建块。手性构筑块通过Wittig反应、加氢和恶唑啉的水解可以很容易地转化为(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、区域选择性甲基化、恶唑啉的水解和1，2-二醇的保护，手性构筑块可以很容易地转化为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.