Lignin as a sustainable feedstock: Upgrading of lignin to chiral synthons

To ensure that we have a sustainable chemical industry, not reliant on petrochemical feedstocks, it is essential that alternative renewable starting materials are used for the production of fine chemicals and pharmaceuticals. The richest source of aromatic compounds is lignin, a highly oxygenated polymer. However, the efficient conversion of lignin into aromatic synthons is still a major challenge. To enable the utilisation of lignin, new methods are needed for its depolymerisation and/or selective modifications, whilst using existing chiral functional groups. This project will develop new routes for the selective modification of lignin, to provide access to valuable chiral compounds via sustainable chemistries. Recent reports have described the aerial oxidation of lignin to e.g Ligninox and depolymerisation to mainly benzoates or deoxygenated compounds (Sch. 1).1,2 However these methods suffer from the use of forcing reaction conditions, toxic reagents and the loss of useful functionalities. In recent work we have identified a method for the selective cyclisation of pentose hydrazones via loss of the C-2 hydroxyl group under acidic or basic conditions and then cyclisation. Here we will apply this approach to the fragmentation and functionalization of lignin and lignin fragments. This strategy has the potential to assist in the selective fragmentation of lignin, while retaining functional groups for further modification using chemical or enzymatic steps.
Proposed research: Initial work will focus on the use of the beta-O-4 and Ligninox model compounds to establish application of the hydrazone methodology to cleave the O-aryl ether bond, and introduce either a hydroxyl group or another nucleophile (Nuc) (Sch. 2). For the beta-O-4 model lignin initial oxidation will be carried out using alcohol dehydrogenase (ADH) libraries available (some coexpressed with the NADH recycling co-factor) or a chemical oxidation method, with subsequent hydrazone formation and cleavage. Compounds obtained, both the phenolics and hydrazones, will be separated using resins for further synthetic manipulations. These include hydrazone hydrolysis (Amberlyst) and reaction with available norcoclaurine synthases (NCSs), transaminases (TAms), and transketolases (TKs) to give single isomer products.4 Similarly, with Ligninox, hydrazone formation, ether cleavage and addition of Nuc, hydrolysis to the ketone and reaction with e.g. TAms will give chiral amines: products accessible from these synthons include amides and cyclic amines, epoxides and aziridines. These are representative conversions: notably only the bioconversion of lignin-derived
vanillin to the corresponding achiral amine using TAms has been reported highlighting the significant potential of biomass-chemistry-biocatalysis strategies to access medicinally relevant compounds. Biocatalytic systems can uniquely give single isomer chiral compounds with exquisite stereocontrol.