ENANTIOSELECTIVE SYNTHESIS OF CHIRAL AMINES

大量具有生物和药理意义的 化合物含有胺官能团。示例包括 非蛋白质来源的氨基酸、生物碱和氨基醇。 这些化合物的生物活性几乎总是 仅限于一种对映体。该方法的发展 不需要拆分外消旋中间体 对映体纯产物的高效化学合成 一个极具吸引力的领域。这份提案描述了 开发一种新的对映选择性通用方法的研究 氨基酸和其他胺类天然产物的合成。这个 项目基于对反应类型的修改 以前仅用于合成外消旋胺 衍生品。这些修改将为发电提供 具有极高立体选择性的手性中心 成功的初步研究证明了这一点。 该项目的设计是基于已知的化学物质 酰亚胺和酰亚胺离子作为反应性亲电剂。我们 将利用手性烷氧基作为酰基 这些中间体。这些亲电体的前驱体 将通过电化学氧化产生 N-烷基化合物。一个关键的特点将是对 几种手性助剂对这类药物的有效性 不对称诱导。只有已知的系统非常 结构相关的高效手性助剂 将对中间体进行检查。 手性的酰亚胺离子将被碳捕获 亲核试剂，如三甲基硅氰化物(改良Strecker 合成)、芳烃和活化烯，以得到新的 含有一个或多个新的手性中心的氨基甲酸酯结构。 这些反应素的立体选择性将是 手性助剂的非对映界面选择性 活性中间体的构象。它是 预计其中许多项目的非对映选择性 反应会非常强烈，所以繁琐的分离 非对映异构体将不是必要的。氨基甲酸酯的裂解 新产品中的功能化将使手性再生 乙醇(手性助剂)和释放光学活性 胺类产品。这些方法将被应用于合成 非同寻常的非蛋白质来源的氨基酸、氨基醇和 生物碱。

Large numbers of biologically and pharmacologically important compounds contain an amine functionality. Examples include non-proteinogenic amino acids, alkaloids, and amino alcohols. The biological activity of these compounds is almost always restricted to one enantiomer. The development of mehtods which do not require resolution of racemic intermediates for efficient chemical synthesis of enantiomerical pure products is an area of considerable interest. This proposal describes research to develop a new general method for enantioselective synthesis of amino acids and other amine natural products. The project is based upon the modification of reaction types previously used only for the synthesis of racemic amine derivatives. These modifications will provide for generation of chiral centers with extremely high stereoselectivity as demonstrated by successful preliminary studies. The project design is based on the known chemistry of acylimines and acyliminiumions as reactive electrophiles. We will utilize a chiral alkoxycarbonyl group as the acyl group in these intermediates. The precursors to these electrophiles will be generated either by electrochemical oxidatin of N-alkyl-compound. A key feature will be the study of the effectiveness of several chiral auxiliaries for this type of asymmetric induction. Only systems known to be extremely efficient chiral auxiliaries in structurally related intermediates will be examined. The chiral acyliminium ions will be captured by carbon nucleophiles such as trimethylsilylcyanide (modified Strecker synthesis), arenes, and activated alkenes to give a new carbamate structure containing one or more new chiral centers. The stereoselectivity of these reactins will be a function of both the diastereofacial selectivity of the chiral auxiliaries and the conformation of the reactive intermediates. It is expected that the diastereoselectivity in many of these reactions will be extremely high so the tedious separation of diastereomers will not be necessary. Cleavage of the carbamate functinality in the new product will regenerate the chiral alcohol (chiral auxiliary)and liberate the optically active amine product. These methods will be applied to the synthesis of unusual non-proteinogenic amijno acids, amino alcohols, and alkaloids.