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

为了确保我们有一个可持续的化学工业，而不是依赖石化原料，至关重要的是使用替代的可再生起始材料来生产精细化学品和药品。芳香族化合物的最丰富来源是木质素，这是一种高含氧量的聚合物。然而，木质素高效转化为芳香族合成子仍然是一个重大挑战。为了能够利用木质素，需要在使用现有手性官能团的同时，对其进行解聚和/或选择性修饰的新方法。该项目将为木质素的选择性修饰开辟新的途径，通过可持续的化学反应提供有价值的手性化合物。最近的报道描述了木质素在空气中氧化成木质素，并解聚成主要是苯甲酸酯或脱氧化合物(SCH)。1).1，2然而，这些方法存在使用强制反应条件、有毒试剂和丧失有用功能的问题。在最近的工作中，我们已经确定了一种方法，通过在酸性或碱性条件下失去C-2羟基，然后环化来选择性环化戊糖肼类化合物。在这里，我们将把这种方法应用于木质素和木质素碎片的碎裂和功能化。这一策略有可能帮助木质素的选择性裂解，同时保留官能团，以便通过化学或酶步骤进行进一步的修饰。建议的研究：初步工作将集中在使用β-O-4和Ligninox模型化合物来建立肼类方法的应用，以裂解O-芳基醚键，并引入一个羟基或另一个亲核试剂(Nuc)(SCH)。2)。对于β-O-4模型，木质素的初始氧化将使用可用的乙醇脱氢酶(ADH)文库(其中一些与NADH循环辅助因子共表达)或化学氧化方法进行，随后形成联氨和裂解。得到的化合物，包括酚类和肼类，将使用树脂分离，以进行进一步的合成操作。这些反应包括酰肼水解(Amberlyst)和与可利用的去甲黄酮合酶(NCSs)、转氨酶(TAMs)和转酮醇酶(TKS)反应，得到单一的异构体产物。4类似地，对于Ligninox，Hydrazone的形成，乙醚的裂解和Nuc的加入，水解酮和与TAMS的反应将得到手性胺：从这些合成子可以获得的产品包括酰胺和环胺、环氧化物和氮杂环。这些都是具有代表性的转化：值得注意的是，只有报道使用TAMS将木质素衍生的香兰素生物转化为相应的无手性胺，这突显了生物质-化学-生物催化战略在获取医学相关化合物方面的巨大潜力。生物催化体系可以独特地得到具有精细立体控制的单异构体手性化合物。

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-derivedvanillin 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.