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

点击翻译按钮获取中文摘要

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.