A new, catalytic strategy for piperidine syntheses and a unified approach to the synthesis of sparteine alkaloids

哌啶合成的新催化策略和金雀花生物碱合成的统一方法

• 批准号: 1949469
• 金额: --
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2017
• 资助国家: 英国
• 起止时间: 2017 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1949469
• 关键词: new; catalytic; strategy; piperidine; syntheses

A wide range of natural products also contain chiral piperidine moieties - especially alkaloids. Since natural products frequently display biological activity, they are important leads for or precursors to pharmaceutical compounds. As a result of this, methodologies that facilitate access to chiral piperidines are of great value to the pharmaceutical industry; these methodologies enable the development of new drugs and the treatment of disease. In this project, we aim to develop a new strategy for the synthesis of chiral piperidines. Sparteine is an alkaloid of considerable value to chemists, as a ligand in a variety of asymmetric metal-mediated processes. In addition to its synthetic applications, sparteine also possesses medicinal properties: it has long been known as an antiarrhythmic agent, and recent research shows that it also acts as an anticonvulsive. Extraction of sparteine from plants enabled access to this compound for many years. In around 2010, however, this changed: sparteine became completely unavailable on the market. Since then, access has been restored, but the price of sparteine has hugely increased, and the compound remains scarce. It is clear that we cannot rely on traditional extraction procedures in the production of this compound. Extraction techniques are also highly wasteful, producing tens of litres of solvent waste per gram of alkaloid. While total syntheses of sparteine have been achieved, they are - at best - very wasteful, and can only produce reasonable quantities of one enantiomer of sparteine. No method currently exists for the synthesis of both enantiomers and all other diastereoisomers of sparteine - compounds that are much less well-known. Given the known value of sparteine as a ligand and in medical research, we believe that it is important that a new route towards all sparteine alkaloids be developed. In achieving this, we aim to increase access to sparteine, and enable research into the less well-known diastereoisomers of sparteine as ligand platforms and compounds of possible medicinal relevance.Proposed solution and methodologyBy making use of a catalytic azide reduction developed by the Denton group, we intend to trigger asymmetric ring closure to access a wide variety of enantiomerically enriched piperidines. Once the efficacy of this methodology has been established, we aim to apply this chemistry in the synthesis of a number of alkaloid targets. In addition to target syntheses, we also hope to expand the ring-closing methodology to include other ring sizes. Our proposed synthesis of sparteine will make use of the above methodology, as well as a number of other catalytic methodologies. We anticipate that this will allow us to develop a new, efficient synthesis of all sparteine alkaloids, in which we can match the appropriate piperidine coupling partners to build any single diastereoisomer of sparteine.

许多天然产物也含有手性哌啶基团，特别是生物碱。由于天然产物经常表现出生物活性，它们是药物化合物的重要先导或前体。因此，便于获得手性哌啶类药物的方法对制药业具有重要价值；这些方法使新药开发和疾病治疗成为可能。在这个项目中，我们的目标是开发一种新的手性哌啶类化合物的合成策略。苦马豆碱是一种对化学家有相当价值的生物碱，在各种不对称金属介导的过程中作为一种配体。除了它的合成应用，司马汀还具有药用价值：长期以来，它一直被认为是一种抗心律失常的药物，最近的研究表明，它还具有抗惊厥的作用。多年来，从植物中提取斯马豆碱使人们能够接触到这种化合物。然而，在2010年左右，情况发生了变化：司马汀在市场上完全买不到了。自那以后，人们恢复了使用，但司马汀的价格大幅上涨，这种化合物仍然很稀缺。显然，在生产这种化合物时，我们不能依赖传统的提取程序。提取技术也非常浪费，每克生物碱会产生数十升的溶剂浪费。虽然已经实现了斯马豆碱的全合成，但它们充其量是非常浪费的，只能生产合理数量的斯马豆碱的一个对映体。目前还不存在同时合成对映体和所有其他非对映异构体的方法，这些化合物的知名度要低得多。鉴于司马豆碱作为一种配体和在医学研究中的已知价值，我们认为开发一条通向所有司马豆碱生物碱的新路线是很重要的。为了实现这一目标，我们的目标是增加对司马豆碱的获得，并使人们能够研究作为配体平台的不太知名的非对映异构体以及可能具有药用价值的化合物。建议的解决方案和方法通过利用Denton小组开发的催化叠氮还原，我们打算触发不对称环闭合来获得各种不对称富含对映体的哌啶类化合物。一旦这种方法的有效性被确立，我们的目标是将这种化学应用于一些生物碱靶标的合成。除了目标合成外，我们还希望将闭环方法扩展到包括其他环尺寸。我们提出的合成斯马豆碱的方法将使用上述方法，以及其他一些催化方法。我们预计，这将使我们能够开发一种新的、有效的合成所有司马豆碱的方法，其中我们可以匹配适当的哌啶偶联伙伴来构建任何单一的司马豆碱的非对映异构体。