Target-Oriented Synthesis of the Prostacyclin Derivative Beraprost

前列环素衍生物贝前列素的靶向合成

• 批准号: 239898471
• 负责人: Professorin Dr. Nina Schützenmeister
• 金额: --
• 依托单位: School of Chemistry
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2013-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/239898471?language=en
• 关键词: Target; Oriented; Synthesis; Prostacyclin; Derivative

The aim of the proposed project is the target-oriented, enantioselective synthesis of the prostacyclin beraprost, whose sodium salt is already used as a drug to treat secondary pulmonary hypertension. Therefore, this project has a high societal impact since there is no enantioselective synthesis of beraprost so far.Beraprost is a tricyclic prostacyclin derivative with a dihydrobenzo[b]furan motif, which is annulated to a cyclopentane ring. This tricyclic backbone is substituted with two side-chains, which are introduced during the synthesis. Altogether, beraprost has six stereogenic centers, whereof four are present at the cyclopentane ring.The proposed synthesis starts with the enantioselective construction of the two annulated five-membered rings. The key step of the synthesis is the L-proline and dibenzylammonium trifluoroacetate catalyzed domino aldol reaction reported previously. Further retrosynthetic analysis of the molecule provides two possible synthetic pathways, which should be investigated during the project. Finally, the developed synthesis will be applied in the preparation of further prostacyclin analogues for the construction of new, active substances of this class.

拟议项目的目的是靶向、对映选择性地合成前列环素贝拉前列素，其钠盐已被用作治疗继发性肺动脉高压的药物。因此，该项目具有很高的社会影响，因为到目前为止还没有对映体选择性地合成贝拉前列素。贝拉前列素是一种带有二氢苯并呋喃基序的三环前列环素衍生物，其环状结构为环戊环。这个三环主链被两个侧链取代，在合成过程中引入了这些侧链。总而言之，贝拉前列素有六个立体中心，其中四个存在于环戊烷环上。建议的合成始于两个环状五元环的对映选择性结构。合成的关键步骤是先前报道的L-脯氨酸和三氟乙酸二苄基铵催化的多米诺-羟醛反应。对分子的进一步逆合成分析提供了两条可能的合成途径，应该在项目期间进行研究。最后，开发的合成将用于制备进一步的前列环素类似物，用于构建这类新的活性物质。