New Synthetic Methods

Over the past few years we have been developing a synthetic programme aimed at the direct synthesis and exploitation of highly functionalised aziridines as versatile functionalised building blocks for complex molecule synthesis. 

As part of this programme, we needed to develop a direct synthesis of a range of functionalised aliphatic aziridines in a stereoselective manner. We have therefore extended the known sulfur ylide addition to aryl aldimines to encompass alkyl, and even ketimine substrates. Further, by using the chiral tert-butylsulfinyl group on nitrogen, we have been able to access aziridines in high diastereoselectivity, and achieve deprotection to reveal the NH aziridines.

The trioxadispiroketal functionality is present in a number of biologically active marine natural products, such as the spirolides, the pinnatoxins , the pteriatoxins and the azaspiracids. As such this functionality is of synthetic interest. However, due to its low occurrence relative to other spirocyclic groups, limited research has been carried out into the assembly of such structures. Our methodology employs a bromonium source to effect an oxidative tandem cyclisation of two proximal hydroxyl groups onto a central furan core allowing direct access to the [5,5,5]-trioxadispiroketal and the [6,5,6]-trioxadispiroketal ring systems. We originally developed this method with the synthesis of azaspiracid in mind - below is shown our model study. Azaspiracid is a toxin which can accumulate in mussels under certain conditions and therefore enter the food-chain. Mussels with toxic levels of azaspiracid have been found off the coasts of England, Wales, Ireland and Norway. To date there have been several fatalities from people eating contaminated mussels. A total or partial synthesis of azaspiracid could lead to better methods of detection of this hazardous material.

We are also interested in the discovery and development of new types of reactivity of organic compounds. The tandem reactions of symmetrical trifunctional substrates are proving to be a fertile platform for this. During a programme directed at the synthesis of a natural product, halichlorine, we uncovered a new method for the formation of a pyrrolidin-1,2-dione. We are currently investigating the generality of this unusual reaction.

Another strategy for the concise synthesis of complex molecules is the use of so-called Multi-Component Reactions (MCR). In these reactions three or more compounds come together to form a complex molecule in a predictable way and in a single step. We have recently developed a multi-component coupling protocol for the direct asymmetric synthesis of sulfinimines. We further developed this procedure into a five component one-pot synthesis of chiral amines, published in J. Org. Chem.

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Direct Synthesis of Aziridines

A New Synthesis of Dioxaspiroketals

Discovery of New Reactions

Multicomponent Reactions