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Next Generation Enzymatic and Integrated Catalytic Approaches for Amide Synthesis

酰胺合成的下一代酶促和集成催化方法

基本信息

批准号：
EP/V048929/1
负责人：
Jason Micklefield
金额：
$ 25.76万
依托单位：
University of Manchester
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2021
资助国家：
英国
起止时间：
2021 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=EP%2FV048929%2F1
关键词：
Next Generation Enzymatic Integrated Catalytic

项目摘要

New routes to pharmaceuticals and other advanced materials are urgently required for a sustainable future. In this project we aim to develop novel, more efficient and sustainable methods for constructing amide bonds, which are common in many leading pharmaceuticals, agrochemicals, polymers and other valuable materials. Typically, amides are constructed synthetically from carboxylic acids and amines using well established coupling reagents. Although this traditional approach is widely used, it is extremely wasteful, lacks selectivity and uses toxic reagents. Coupling of carboxylic acids and amines typically requires one equivalent or more of coupling reagents, creating considerable waste as well as problems in reaction purification. Protecting groups are often necessary to block other reactive functionality in the precursors, so multiple steps (protect-couple-deprotect) are usually required to generate a single amide bond, consuming further expensive and deleterious reagents. Racemization/epimerization is also a common problem when coupling chiral precursors. This loss of stereochemistry is problematic in the synthesis of drugs which need to be produced as single stereoisomers. Finally, traditional amide coupling reactions typically employ dipolar aprotic solvents or chlorinated solvents, which present further safety issues and increased costs associated with their disposal.In this project we aim to use a biotechnology-based approach to deliver amides in a more efficient and environmentally sustainable manner. To achieve this, we will explore two complementary methods for producing amides. First, we aim to engineer natures catalysts (enzymes) to create new enzyme variants (mutants) that can couple a wide range of acid and amine substrates. In addition, we plan to combine enzymes with transition metal catalyst to create new integrated catalytic approaches to amides. By combining the best of enzymatic and chemocatalysis, we aim to open new transformations and routes to valuable amides that would be inaccessible using existing methods. Nature has created a number of ways to couple acids and amines to make amide bonds with the most common methods relying on a molecule called ATP to activate the carboxylic acid group facilitating attack of the amine substrate. Such enzymes are called amide ligases and they possess binding sites for both the carboxylic acid and amine substrates. Normally the amide ligases nature provides have narrow substrate scope. We propose engineering both binding sites of the ligase enzymes to create new mutant enzymes that can couple a much wider range of substrates. The new enzymes will work in water, require no additional expensive or toxic reagents and can therefore be utilised for the more environmentally and cost-effective synthesis of valuable amides required for production of pharmaceuticals and other important molecules. In addition to amide ligases enzymes, we will also explore the utility of a different class of enzyme, the nitrile hydratases (NHase), for amide synthesis. NHase add water to nitriles (molecules with -CN groups) producing to primary amides (-CONH2). To broaden the scope of NHase we aim to combine these enzymes with a transition metal catalyst that can install a functional group on the primary amide to create more diverse secondary amides (-CONHR) which are typically found in pharmaceuticals etc. Normally combining enzymes with metal catalysts is problematic as the two catalysts are incompatible. For example, metals can bind to enzymes and deactivate the catalysts. To overcome this problem, we have devised a range of methods for compartmentalising enzymes and metal catalysts, in such a way that the two can be combine in a single (one-pot) reaction. This can also provide more direct routes to amides from alternative feedstocks (precursors).

为了可持续的未来，迫切需要新的制药和其他先进材料的生产路线。在这个项目中，我们的目标是开发新的，更有效和可持续的方法来构建酰胺键，这在许多领先的药物，农用化学品，聚合物和其他有价值的材料中很常见。通常，酰胺是使用公认的偶联剂由羧酸和胺合成构建的。虽然这种传统的方法被广泛使用，但它非常浪费，缺乏选择性并使用有毒试剂。羧酸和胺的偶联通常需要一当量或更多的偶联试剂，产生相当大的浪费以及反应纯化中的问题。保护基团通常是阻断前体中的其他反应性官能团所必需的，因此通常需要多个步骤（保护-偶联-脱保护）来产生单个酰胺键，从而消耗进一步昂贵和有害的试剂。外消旋/差向异构化也是偶联手性前体时的常见问题。这种立体化学的损失在需要作为单一立体异构体产生的药物的合成中是有问题的。最后，传统的酰胺偶联反应通常使用偶极非质子溶剂或氯化溶剂，这带来了进一步的安全问题，并增加了与其处置相关的成本。在本项目中，我们的目标是使用基于生物技术的方法，以更有效和环境可持续的方式提供酰胺。为了实现这一目标，我们将探索两种互补的生产酰胺的方法。首先，我们的目标是设计天然催化剂（酶），以创造新的酶变体（突变体），可以耦合广泛的酸和胺底物。此外，我们计划将联合收割机与过渡金属催化剂相结合，以创造新的集成催化酰胺的方法。通过结合最好的酶和化学催化，我们的目标是开辟新的转化和路线，以有价值的酰胺，将无法使用现有的方法。自然界已经创造了许多方法来偶联酸和胺以形成酰胺键，其中最常见的方法依赖于称为ATP的分子来激活羧酸基团，从而促进胺底物的攻击。这种酶被称为酰胺连接酶，它们具有羧酸和胺底物的结合位点。通常酰胺连接酶的性质提供了狭窄的底物范围。我们建议工程连接酶的两个结合位点，以创建新的突变酶，可以耦合更广泛的底物。新的酶将在水中工作，不需要额外的昂贵或有毒的试剂，因此可以用于更环保和成本有效的合成药物和其他重要分子生产所需的有价值的酰胺。除了酰胺连接酶之外，我们还将探索用于酰胺合成的不同种类的酶腈水合酶（NHase）的效用。NHase将水加到腈（具有-CN基团的分子）上，产生伯酰胺（-CONH 2）。为了拓宽NHase的范围，我们的目标是将这些酶与过渡金属催化剂结合，该催化剂可以在伯酰胺上安装官能团以产生更多样化的仲酰胺（-CONHR），其通常在药物等中发现。通常将酶与金属催化剂结合是有问题的，因为这两种催化剂不相容。例如，金属可以与酶结合并使催化剂失活。为了克服这一问题，我们设计了一系列方法，用于将酶和金属催化剂区室化，使得两者可以在单个（一锅）反应中联合收割机。这也可以提供从替代原料（前体）到酰胺的更直接途径。