New approaches to the synthesis of sulfoximines

Phyllanthus emlica L. (Euphorbiaceae), a shrub or tree growing in subtropical and tropical areas of the People's Republic of China, India, Indonesia, and the Malay Peninsula, has been used widely for its anti-inflammatory and antipyretic effects in many local traditional medicinal systems, such as Chinese herbal medicine. A team of chemists working in Japan and China isolated a number of discrete substances from the roots of the plant, and determined the molecular structure of these compounds through careful spectroscopic and chemical analysis. The core of a number of these compounds, named phyllaemblic acid, has a structure similar to a number of related compounds with potent biological activity, and contains a five and a six-membered ring system containing oxygen joined together at a single carbon atom (a "spirocycle").
A chemical synthesis of phyllaemblic acid would allow for further investigations into its potential biological activity, but has never been previously reported. This project will address the first total synthesis of the natural product by exploiting an element of symmetry (a mirror plane) within a section of the molecule. This greatly simplifies its total synthesis since the molecule can conveniently be derived from two portions of similar complexity, only one of which is "chiral" (has a non-superimposable mirror image).

This strategy will be extended to the first syntheses of the more complex related natural products phyllaemblicins A-C, which contain phyllaemblic acid attached to different sugars through an ester group. Again the biological activity of these natural products has barely been investigated and will be made possible through total synthesis.

Stereoselective synthesis remains central to modern organic chemistry, and new methodology must continually be developed in order to prepare more structurally complex materials. Beneficiaries in the UK include the pharmaceutical industry, which requires new means to efficiently prepare chiral molecules. UK academia will also benefit from the high impact the combination of new methodology applied to a major natural product synthesis has within the international organic chemistry community - it is still relatively rare that the first synthesis of a natural product emanates from these shores. The novel diastereotopic group selection strategy central to this project will further encourage other groups to consider such potentially powerful reactions in their own research. A large number of new "natural product like" compounds will be produced in this study that may have beneficial biological activity themselves, which may ultimately increase the quality of life in the UK. Natural product synthesis represents an ideal training for a PhD student in modern organic chemistry, as by its very nature it involves exposure to and mastery of a wide range of transformations and theories. The PhD student on this project will develop the experience and expertise required to enter a career in either the pharmaceutical industry or in academia.