Conversion of Biomass-Based Compounds into Added-Value Chemicals: Synthetic Modifications of Quinic Acid

Fossil-based resources currently provide the energy and feedstock chemicals to sustain our ways of living. A transition from crude oil to biorenewables is essential to provide sustainable energy sources and alternative routes for fine chemicals in the future. Such transition is challenging due to the over-functionalized nature of biomass-based molecules, as they have an oxygen-containing group in almost every carbon. In turn, the fossil-based chemicals we currently use are under-functionalized, therefore the methods for exploiting these resources are very different. In light of this, selected current methods for defunctionalization of biomass-based molecules are surveyed in this thesis, followed by review on the synthetic manipulation of quinic acid, a biomass- derived cyclitol.

Quinic acid occurs widely in plants and microorganisms and can serve as starting material in the synthesis of chiral compounds. This thesis studies the valorization of quinic acid and is focused on the removal of hydroxyl groups permitting the formation of chiral building blocks for use in the synthesis of natural products.

The use of tris(pentafluorophenyl)borane combined with hydrosilanes is a contemporary tool in the site selective deoxygenation of biomass-derived feedstocks and was explored in the valorization of quinic acid. The borane-catalyzed hydrosilylation through a silyloxonium intermediate led to formation of unforeseen synthetic fragments by diversification of reaction conditions. The divergent defunctionalization provided access to chiral aldehydes, alcohols and tetrahydrofuran derivatives and eventually expanded to the formal synthesis of homocitric acid. The deoxygenation mechanism was rationalized by Density Functional Theory calculations.

O,O-Silyl migrations across quinic acid derivatives were observed during the deoxygenation experiments. Such migrations were further studied and optimized, resulting in selective formation of silylated regioisomers. The migration reactions were observed to be dependent on the reaction conditions and silyl substituents. One of the regioisomers obtained was further modified to build the first total synthesis of an African ant cyclitol and the formal synthesis of kidney disease drug VS-105. A redesigned concise total synthesis of epimeric natural carbasugars isolated from Streptomyces lincolnensis is presented in this thesis. The synthesis had as key steps the regioselective reduction of quinic acid and the epimerization of one of the intermediates to create a divergent point.

Lastly, several quinic acid derivatives were synthesized, and their biological properties briefly assessed, leading to the identification of a particular derivative as a promising lead for the development of glioblastoma multiforme chemotherapeutic agents.

The findings presented in this thesis deepen the versatility of quinic acid as a chiral scaffold. Although quinic acid has been used as a chiral pool molecule for decades, application of modern synthetic methods provides a powerful tool for diversification of common intermediates. The protocols presented also expand the group of chiral fragments that can be obtained from biorenewables. The facility of creating a divergent point also enables studying how structural modification of quinic acid derivatives correlates with the bioactivity.