CAREER: Chemoenzymatic Synthesis of Complex Polycyclic Alkaloids Enabled by A-Ketoglutarate Dependent Iron Enzymes

职业：通过 A-酮戊二酸依赖性铁酶实现复杂多环生物碱的化学酶法合成

• 批准号: 2338495
• 负责人: Chi Ting
• 金额: $ 77万
• 依托单位: Brandeis University
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-02-01 至 2029-01-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2338495&HistoricalAwards=false
• 关键词: CAREER; Chemoenzymatic; Synthesis; Complex; Polycyclic

With support of the Chemical Synthesis program in the Division of Chemistry, Chi Ting of Brandeis University is studying the development of new strategies for the synthesis of a class of naturally occurring molecules that are referred to as alkaloids. Many of these molecules are challenging to isolate from natural sources, resulting in limited quantities being available to study. Specifically, this work will couple organic synthesis with enzymology (biocatalysis) to prepare alkaloids in sufficient quantities for their further study, particularly their study for therapeutic purposes. The biocatalysis that the Ting group is examining modifies relatively complex molecular intermediates and by doing so, allows them to directly access the alkaloids. In addition to the research plan, outreach activities are planned to introduce organic chemistry to middle school students in Waltham, Massachusetts. These activities will showcase the presence of natural products in everyday life, and introduce students to molecular structure. The overarching goal of these activities is to engage students early on in chemistry and especially organic chemistry in so doing, initiate interest in pursuing science professionally. The Ting lab is enabling the total synthesis of complex, polycyclic alkaloids by incorporating enzyme-catalyzed reactions at a late stage into their total synthesis efforts. Their approach is not only conceptually different than traditional total synthesis efforts because of the importance of biocatalysis in the synthetic design. The approach also differs from most chemoenzymatic synthetic methods in that these typically involve the biocatalyst-facilitated synthesis of earlier stage synthetic building blocks, often with control of absolute stereochemistry. There is currently great interest in chemical biology and medicinal chemistry circles in expanding the use of late stage functionalization into the repertoire of chemoenzymatic synthesis. Much activity has been directed at late stage enzymatic halogenation, for example. The work proposed here goes beyond such transformations to develop more fully the area of late stage peroxidation. This strategy has the potential to be highly enabling for the generation of complex, bioactive molecules, especially those that contain relatively sensitive peroxide functionalities.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

在化学系化学合成项目的支持下，布兰迪斯大学的Chi Ting正在研究开发一类天然存在的分子的新策略，这些分子被称为生物碱。这些分子中的许多分子很难从天然来源中分离出来，导致可用于研究的数量有限。具体而言，这项工作将有机合成与酶学（生物催化）相结合，以制备足够数量的生物碱，用于进一步研究，特别是用于治疗目的的研究。Ting团队正在研究的生物催化作用改变了相对复杂的分子中间体，并通过这样做，使它们能够直接获得生物碱。除了研究计划外，还计划开展外联活动，向马萨诸塞州沃尔瑟姆的中学生介绍有机化学。这些活动将展示天然产品在日常生活中的存在，并向学生介绍分子结构。这些活动的总体目标是让学生尽早参与化学，特别是有机化学，从而激发他们对专业追求科学的兴趣。Ting实验室通过在后期阶段将酶催化反应纳入其总合成工作中，实现了复杂多环生物碱的全合成。由于生物催化在合成设计中的重要性，他们的方法不仅在概念上不同于传统的全合成努力。 该方法也不同于大多数化学酶合成方法，因为这些方法通常涉及生物催化剂促进的早期合成结构单元的合成，通常控制绝对立体化学。 目前，化学生物学和药物化学界对将后期功能化的使用扩展到化学酶促合成的全部剧目中有很大的兴趣。 例如，许多活性已经针对后期酶促卤化。 这里提出的工作超越了这种转变，以更充分地发展后期过氧化作用的领域。 这一战略有可能高度促进复杂的生物活性分子的生成，特别是那些含有相对敏感的过氧化物官能团的分子。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。