Foldamer-based pyridoxal phosphate mimics as organocatalysts for transamination reactions

Details

Supervisors

Singleton, Michael L.

Faculty

Faculté des sciences

Degree label

Master [120] en sciences chimiques, à finalité approfondie

Abstract

Pyridoxal-5’-phosphate, the biologically active form of vitamin B6, has been intriguing scientists for decades thanks to its ability to catalyze many different biological reactions involving amine substrates. This coenzyme can bind to more than 140 enzymes to help them in their function, each of them catalysing its own reaction due to the difference in the environment. Indeed, the selectivity of PLP has been demonstrated to be highly dependent on the environment around the reaction center. Depending on the residues interacting with this reaction center and thus, depending on the specific 3D folding of each enzyme, the selectivity of PLP is tuned, leading to a highly versatile catalyst. Inspired by PLP, this master’s thesis aims to develop a new type of PLP-like organocatalyst where the local environment around the active site can be specifically controlled. For this, we make use of foldamers, oligomers able to fold on themselves to adopt a specific 3D structure, similar to what occurs with enzymes. These structures combine the best of enzymes and organocatalysts by allowing specific placement of relevant functional groups on well-defined and stable backbones. This makes them ideal tools for studying how the change in environment induced by the specific folding of foldamers around a PLP-mimic influences the reactivity. This master’s thesis therefore describes the synthesis of a trimeric sequence containing a PLP analogue thanks to a combinatorial approach. The aldehyde group of the PLP-mimic was obtained by direct functionalization of the trimer, allowing to avoid additional protecting and deprotecting steps and providing a new post-synthetic functionalization example for AOF. The catalytic potential of this new trimeric PLP-mimic towards a transamination reaction with benzylamine and a sacrificial ketone was investigated. We first attempted to optimize the conditions for this reaction with the monomeric PLP-mimic and then compared the reactivity of the monomeric and trimeric PLP analogues. Based on what we observed, the trimer can perform this reaction faster than the monomer, giving one of the rare AOF acting as a catalyst. These promising results provide a new type of reactivity not previously reported for foldamers and open new possibilities for organocatalyst design.