Synthetic Study on Biologically Active Natural Products containing alpha, alpha-Disubstituted alpha-Amino Acid Structures

近年来，具有α， α -二取代α -氨基酸结构的天然产物，如乳酸菌素，鞘菌素和肉豆蔻素已被分离出来。由于其有趣和重要的生物活性（神经营养、抗生素、免疫抑制和酶抑制），α， α -二取代a-氨基酸衍生物有望成为新药的强有力的先导化合物。本课题研究了以碳水化合物为原料合成α， α -二取代α -氨基酸衍生物的新方法，即通过丙基三氯乙酸酯重排（Overman重排）立体选择性生成具有氨基官能团的四取代碳。由醛己糖（d -葡萄糖和d -甘露糖）制备的烯丙醇衍生物转化为相应的三氯乙酸酯，在140℃加热下进行Overman重排，得到高收率和中等立体选择性（1:2 ~ 1:10）的重排产物（乙烯酰胺）。发现半经验分子轨道计算能够预测重排反应的立体选择性。重排产物中的糖骨架转化为所需的碳骨架，为乳酸菌素的全合成和鞘真菌素F的合成前体以及肉豆素的合成提供原料。该研究为从碳水化合物中提取α -二取代α -氨基酸衍生物提供了新的有效途径。

Recently, natural products with alpha, alpha-disubstituted alpha-amino acid structures, such as lactacystin, sphingofungins, and myriocin, have been isolated. Due to their interesting and important biological activities (neurotrophic, antibiotic, immunosuppressive, and enzyme inhibitory), alpha, alpha-disubstituted a-amino acid derivatives are expected to be potent lead compounds for novel drugs.In this project, novel synthetic approach to alpha, alpha-disubstituted alpha-amino acid derivatives starting from carbohydrates, which involved the stereoselective generation of the tetra-substituted carbon possessing amino functionality by the rearrangement of the allylic trichioroacetimidate (Overman rearrangement) was investigated.Allylic alcohol derivatives prepared from aldohexoses (D-glucose and D-mannose) were converted into corresponding trichioroacetimidates, which underwent Overman rearrangement by heating at 140ﾟC to afford rearranged products (vinyl amides) in high yields and in moderate stereoselectivities (1 : 2 - 1 : 10). Semi-empirical molecular orbital calculations were found to be able to predict the stereoselectivities of rearrangement reactions. The sugar skeleton in rearranged products was transformed to the desired carbon frame work to furnish the total synthesis of lactacystin and the synthesis of the synthetic precursor of sphingofungin F as well as myriocin.This study provided the novel and effective pathway to alpha, alpha-disubstituted alpha-amino acid derivatives from carbohydrates.