Pump up the volume: Foldamers as molecular amplifiers

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different compartments. This cellular compartmentalisation by membranes permits the separation of incompatible catalytic conditions. A similar incompatibility often occurs when attempting to link aqueous biocatalysis with chemocatalysis that has been optimised in organic solvents. Molecular information relays developed in the Webb group could provide an exciting solution to this problem. These relays transmit information along multi-nanometre distances, which allows them to operate simultaneously in aqueous and hydrophobic environments.[1],[2] At their core is an amphiphilic alpha-aminoisobutyric acid (Aib) foldamer that adopts well-defined helical conformations. Incoming information causes a change in structure at the N-terminus (e.g. an M to P helicity switch) that is relayed to the far end of the foldamer. Webb has shown these foldamers can relay chiral information from an aqueous chemical messenger deep into the hydrophobic region of a membrane to produce a spectroscopic output. We now wish to produce chemical messengers using biocatalysis and to replace the spectroscopic output with chemocatalysis. The outcome will be an information relay that amplifies the chiral output from an enzyme by inducing enantioselectivity in a chemocatalyst; producing a synthetic signalling cascade. The Turner lab will provide the first part of the signalling cascade, by screening for potential ligands (carboxylates, phosphates) that can be produced by biocatalytic processes, e.g. by the action of kinases, dehydrogenases etc. Webb and Turner previously found that Candida antarctica lipase B hydrolyses rac-BocProOMe in water to give Boc-D-Pro with high enantioselectivity.[3] This is a known active signalling molecule, but this enzyme has not yet been screened against membrane-embedded foldamers. Similar Aib foldamers can report on the e.e. of mixtures produced through organocatalysis,[4] so alternatives include the kinetic resolution of racemic carboxylates (transformation of one enantiomer into a non-binding product such as an aldehyde, amide or lactone) or the enzymatic transformation of achiral substrates into chiral carboxylates. The next part of the signalling cascade will use Aib foldamers that bear N-heterocyclic carbenes (NHCs) at their C-terminus, which permits access to organometallic catalytic "write heads". The first generation of catalytic "write heads", foldamer-Rh(I) complexes, have been shown in the Webb lab to reduce ketones to chiral alcohols. More catalytic reactions need to be developed (e.g. alkyne hydrosilylation) and other catalytic write-heads, such as Ru(II)-NHC complexes for ROMP, synthesised.The student will receive broad multidisciplinary training. The project will start with the chemical synthesis of Aib foldamer-organometallic complexes and analysis of their catalytic performance in organic solvents, including tolerance to low levels of water. In parallel, ligand screening will be performed and enzymatic systems developed that are compatible with phospholipid vesicles and able to generate enantioenriched carboxylate. Finally a recognition motif will be installed, and the performance of the molecular construct assessed when in vesicles.This project combines chemocatalysis with biocatalysis to create a synergistic chemo/biocatalysis cascade. Furthermore the student will work closely with PDRAs using Aib foldamers in Webb's current EPSRC-funded research in molecular robotics, bolstering efforts in this area.