Enantioselective synthesis of morphine alkaloids

吗啡生物碱的对映选择性合成

• 批准号: 328735723
• 负责人: Professor Dr. Peter Metz
• 金额: --
• 依托单位: Professur für Organische Chemie I
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/328735723?language=en
• 关键词: Enantioselective; synthesis; morphine; alkaloids

The main objective of this project is the enantioselective total synthesis of the morphine alkaloid (-)-codeine. For one, our synthesis of racemic codeine via an intramolecular nitrone cycloaddition shall be modified now in an asymmetric fashion. In this respect, the use of a chiral latent cyclohexadienone is envisaged, which is generated by introducing a temporary thiophenyl group in two complementary scenarios. Furthermore, an alternative strategy for the final steps to codeine is to be tested in order to increase the efficiency of the overall sequence. On the other hand, a first enantioselective route to the morphine alkaloid thebainone A and a conceptually novel transformation of this compound to codeine shall be developed. Again using an intramolecular nitrone cycloaddition as a key process, we were already able to construct the morphinan skeleton of the target compound in racemic form. For enantioselective synthesis, an asymmetric Heck reaction shall now be preferably used, and for conversion into codeine a concise three-step transformation of a thebainone A derivative is planned via an intermediate vinyl epoxide. Realization of this project would not only open a new access to natural morphine alkaloids but also to analogs, which can hardly or not at all be derived from the natural products.

本项目的主要目标是对映选择性全合成吗啡生物碱（-）-可待因。首先，我们通过分子内硝酮环加成反应合成外消旋可待因，现在应该以不对称的方式进行修改。在这方面，设想使用手性潜在环己二烯酮，其通过在两种互补情况下引入临时噻吩基而产生。此外，将测试用于可待因的最后步骤的替代策略，以提高整个序列的效率。另一方面，第一个对映体选择性路线的吗啡生物碱thebainone A和一个概念新颖的转换，这种化合物的可待因应开发。再次使用分子内硝酮环加成作为关键过程，我们已经能够构建外消旋形式的目标化合物的吗啡喃骨架。对于对映选择性合成，现在应优选使用不对称Heck反应，并且对于转化为可待因，计划通过中间体乙烯基环氧化物进行thebainone A衍生物的简明三步转化。该项目的实现不仅为天然吗啡生物碱的开发开辟了新的途径，也为天然产物中几乎不能或根本不能衍生的类似物的开发开辟了新的途径。