Complexity From Symmetry

This programme of work will set out to develop a new strategy for synthesising complex molecules in very short synthetic sequences. This new strategy will combine two techniques that can reduce the number of operations required to synthesise complex molecules: bi-directional synthesis (where a molecule is built up from the middle in two directions at once), and tandem reactions (where a series of reactions are carried out in a cascade, and thus require just one operation). The operation-reducing power of combining these two techniques was shown by us in a recent synthesis of histrionicotoxin, a potent frog toxin that is a useful biological probe for the mechanisms of action of the nervous system.Bi-directional synthesis intrinsically forms symmetrical products. In the case of the synthesis of many compounds of biological or material interest, asymmetric products are required for the correct properties to predominate. Thus we propose to develop a method of desymmetrisation, which we will build-in to the bidirectional synthesis strategy. We will design tandem reactions that react with one end of the symmetrical molecule in one way, and will react in a different manner at the other end of the molecule, thus intrinsically desymmetrising the substrate.Bi-directional synthesis will be used to synthesise a range of symmetrical chain-like molecules with functionality in the middle and functionality at either end. A variety of different tandem reactions will be used to fold these chains in on themselves, creating new, much more complicated molecular scaffolds. This complexity generation will give us new and exciting molecules which can be used to make complex natural products (like the anti-cancer compound lepidiformine, for example), or for use as starting points for the synthesis of un-natural compounds for testing against a range of different biological activities.