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

为了确保我们拥有一个可持续的化学工业，而不是依赖于石化原料，必须使用替代的可再生起始材料来生产精细化学品和药品。芳香族化合物最丰富的来源是木质素，一种高度氧化的聚合物。然而，将木质素有效转化为芳族聚碳酸酯仍然是一个重大挑战。为了能够利用木质素，需要新的方法用于其解聚和/或选择性改性，同时使用现有的手性官能团。该项目将开发木质素选择性改性的新途径，通过可持续的化学方法提供有价值的手性化合物。最近的报道已经描述了木质素的空气氧化为例如Ligninox和解聚为主要的苯甲酸酯或脱氧化合物（Sch.1）。1，2然而，这些方法受到使用强制反应条件、有毒试剂和有用官能团损失的影响。在最近的工作中，我们已经确定了一种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腙的方法。在这里，我们将这种方法应用于木质素和木质素片段的片段化和功能化。这种策略有可能有助于选择性地裂解木质素，同时保留官能团，以便使用化学或酶促步骤进行进一步修饰。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，以建立应用腙方法来裂解O-芳基醚键，并引入羟基或另一种亲核试剂（Nuc）（Sch. 2）。对于β-O-4模型，将使用可用的醇脱氢酶（ADH）文库（一些与NADH再循环辅因子共表达）或化学氧化方法进行木质素初始氧化，随后形成腙并裂解。所获得的化合物，无论是酚类化合物和腙，将使用树脂进行分离，用于进一步的合成操作。这些包括腙水解类似地，使用木质素、腙形成、醚裂解和添加Nuc、水解成酮并与例如TAms反应将得到手性胺：可从这些二酮得到的产物包括酰胺和环胺、环氧化物和氮丙啶。这些是代表性的转换：值得注意的是，只有木质素衍生的香草醛的生物转化为相应的非手性胺使用TAms已被报道，突出了生物质化学生物催化策略的显着潜力，以获得药用相关的化合物。生物催化体系可以独特地合成具有精细立体控制的单一异构体手性化合物。

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.