Current Targets for Total Synthesis
(+)-Phorboxazole B: Is a potent anticancer agent which is no longer available from nature. Our highly convergent approach uses our recent development of the asymmetric Maitland-Japp pyran forming reaction and a novel stereodivergent Michael reaction to rapidly assemble the tetrahydropyran units present. This will enable the individual pyran fragments to be coupled efficiently, minimising the need for further manipulations.
The Pinguisanes: Studies are directed at completing a total synthesis and a biomimetic synthesis of a number of the pinguisane family of sesquiterpenes. These molecules have both antimicrobial activity and insect anti-feedant properties, making them of interest to both medicinal chemists and argochemists a like.
Completed Natural Products
(±)-Centrolobine: Use of a 3 component, one pot reaction for the formation of highly substituted tetrahydropyrans has enabled us to synthesise the antibiotic molecule centrolobine in only 4 steps.
(±)-Civet Cat Secretion: Use of the dihydropyran version of the Maitland-Japp reaction has enabled the diastereoselective synthesis of the molecule found in Civet cat secretion.
(±)-Citreothiopyrane A: Use of a thiopyranone modification of the Maitland-Japp reaction has led to the synthesis of this metabolite of penicillium citreo-viride B. IFO 6200 and 4692, a natural product with plant growth inhibition activity.
New Methodologies
PASE synthesis: We have developed a new pot, atom and step economic (PASE) synthesis of highly substituted tetrahydropyranones, which does not involve a Diels-Alder cyclisation. Our work has delivered two enantioselective versions of this reaction, which generate THPs in 99%e.e. We are now focused on expanding the utility of this reaction to enable the asymmetric synthesis of piperidine rings and structurally diverse 3D-heterocyclic fragments with are of substantial interest to medicinal chemists for the development of new drug molecules.
Origins of Biological Homochirality
A fundamental question of science is how did Life arise on the early Earth? Obviously, for Life to arise all of its building blocks must have been in place. However, there is little evidence on how the essential building blocks of Life, such as carbohydrates, form in the absence of any biological processes, and how did one enantiomer of these molecules come to dominate? We are investigating the use of organocatalysis to provide answers to these questions, specifically in the prebiotic asymmetric formation of carbohydrates. Preliminary studies have already demonstrated that glyceraldehyde, threose and erythrose can be formed in good yields with the highest enantioselectivities reported to-date.
(±)-Diospongin A and B: Application of our stereodivergent oxy-Michael reaction has furnished efficent syntheses of both natural products from a single precursor.
Anthracimycin: With the dire need for new antibiotics being constantly highlighted by both government and health professionals we have initiated studies directed at completing the first total synthesis of anthracimycin. This recently isolated marine natural product has potent antibacterial activity and an unknown mode of action. We aim to produce quantities of the natural product and strutural analogues in order to probe anthracimycin's mode of action and determine whether it has the potential to be a new weapon in the war against antibiotic resistance "superbugs".
