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

许多天然产物也含有手性胡椒碱，尤其是生物碱。由于天然产物经常显示生物活性，它们是药物化合物的重要先导物或前体。因此，易于获得手性哌啶的方法对制药工业具有重要价值；这些方法有助于开发新药和治疗疾病。在本项目中，我们旨在开发一种合成手性哌啶的新策略。Sparteine是一种对化学家具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配体。除了它的合成应用，sparteine也具有药用特性：它一直被认为是一种抗心律失常的药物，最近的研究表明，它也有抗惊厥的作用。多年来，从植物中提取的sparteine使人们能够获得这种化合物。然而，在2010年左右，情况发生了变化：斯巴达丁在市场上完全买不到。从那时起，通道已经恢复，但斯巴达丁的价格大幅上涨，而且这种化合物仍然稀缺。很明显，我们不能依靠传统的提取方法来生产这种化合物。提取技术也非常浪费，每克生物碱产生几十升的溶剂废物。虽然已经实现了sparteine的完全合成，但它们充其量是非常浪费的，并且只能产生合理数量的sparteine的一种对映体。目前还没有一种方法既能合成对映体又能合成spartinine的所有其他非对映异构体，这些化合物的知名度要低得多。鉴于sparteine作为一种配体和在医学研究中的已知价值，我们认为开发一种新的途径来开发所有sparteine生物碱是很重要的。为了实现这一目标，我们的目标是增加对sparteine的获取，并使研究不太知名的sparteine非对映异构体作为配体平台和可能具有医学相关性的化合物成为可能。建议的解决方案和方法：通过利用Denton团队开发的催化叠氮化物还原，我们打算触发不对称环闭合，以获得各种对映异构富集的哌啶。一旦这种方法的有效性已经确立，我们的目标是将这种化学应用于合成一些生物碱目标。除了目标合成外，我们还希望扩展环闭合方法以包括其他环尺寸。我们提出的合成sparteine将利用上述方法，以及其他一些催化方法。我们预计这将使我们能够开发出一种新的，高效的合成所有sparteine生物碱的方法，其中我们可以匹配合适的哌啶偶联伙伴来构建sparteine的任何单一非对映异构体。

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.