New Foldamer Catalysts

在化学系大分子、超分子和纳米化学项目的支持下，威斯康星大学麦迪逊分校的Samuel H. Gellman教授将开发受酶结构多样性启发的折叠体催化剂。酶是一种以蛋白质为基础的大分子，它可以作为生物催化剂，加速生物体内的多种化学反应。由酶催化的一些最著名的反应包括蔗糖转化为葡萄糖和果糖，葡萄糖分解为乙醇和二氧化碳，以及脂肪的水解。另一方面，Foldamers是一种非自然的支架，可以模拟类似蛋白质的构象行为，也可能模拟酶的催化特性。在本项目中，除了常用的天然肽α-氨基酸构建块外，还将使用β-氨基酸制备折叠体。在蛋白质折叠过程中，关键亚基被排列成精确的三维阵列，这是与其他分子结合和催化化学反应所必需的。在这个项目中，有机化学和超分子化学将被专门用于制备双功能和三功能折叠体催化剂，以使有效的官能团结合到螺旋折叠体支架中。然后，合成的催化剂将用于各种金属和非金属催化的碳-碳键形成反应。该项目将为跨学科研究提供优秀的培训，并使年轻学者能够在学术界、工业界或其他环境中从事富有成效的职业。此外，Gellman教授将通过参与研究生招聘和作为戈登研究会议的受托人的活动，继续支持科学界的多样性，公平性和包容性的扩大。该项目将通过检测含有新型活性二联体的α/β-肽，寻求扩大双功能折叠体催化的范围。在第一个总体目标下，将追求三条途径，重点是双功能催化。在第一种途径中，含有新型活性基团的侧链通过共价激活底物发挥作用，特别是，用于α-取代的烯醛亲电激活的肼，以及用于激活醛类进行Stetter反应的噻唑体系或相关杂环，将被纳入折叠体支架中。在第二种途径，旨在通过氢键或阳离子-π相互作用非共价激活底物的侧链将被探索。第三种途径将侧重于添加联吡啶或三吡啶单元，这些单元将用于与镍络合并随后进行醛的α-芳基化。在第二个目标中，团队将寻求利用文件夹支架的模块化，以允许三个功能组协同工作，以促进单个转换。该项目旨在开发受酶结构多样性启发的新型催化剂。精确控制文件夹内多个反应位点位置的能力也为使用这些酶模拟物进行协同催化提供了令人兴奋的机会。该奖项反映了美国国家科学基金会的法定使命，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。

With the support of the Macromolecular, Supramolecular and Nanochemistry program in the Division of Chemistry, Professor Samuel H. Gellman of the University of Wisconsin-Madison will develop foldamer catalysts that are inspired by the structural diversity of enzymes. Enzymes are large protein-based macromolecules that act as biological catalysts by accelerating numerous chemical reactions in living organisms. Some of the most well known reactions catalyzed by enzymes include conversion of cane sugar into glucose and fructose, breaking of glucose into ethyl alcohol and carbon dioxide, and hydrolysis of fats. Foldamers, on the other hand, are unnatural scaffolds that mimic protein-like conformational behavior and potentially also the catalytic properties of enzymes. In this project, foldamers will be prepared using β-amino acids in addition to the usual α-amino acid building blocks for natural peptides. During the protein folding process, key subunits are arranged into the precise three-dimensional arrays that are essential for binding to other molecules and catalyzing chemical reactions. In this project, organic and supramolecular chemistries specifically tailored to enable efficient functional group incorporation into helical foldamer scaffolds will be utilized to prepare bifunctional and trifunctional foldamer catalysts. The synthesized catalysts will then be utilized in variety of metal and non-metal catalyzed carbon-carbon bond forming reactions. This project will provide excellent training in interdisciplinary research and enable young scholars to undertake productive careers in academia, industry, or other settings. Additionally, Professor Gellman will continue to support expansion of diversity, equity, and inclusion in the scientific community through his involvement in graduate student recruitment and through his activities as a Trustee of the Gordon Research Conferences.This project will seek to expand the range of bifunctional foldamer catalysis by examining α/β-peptides containing new types of reactive diads. Three paths will be pursued under the first general goal, focusing on bifunctional catalysis. In the first path, side chains containing new types of reactive groups that function via covalent activation of substrates, specifically, hydrazides for electrophilic activation of α-substituted enals, and thiazolium systems or related heterocycles for activation of aldehydes toward Stetter reactions, will be incorporated into foldamer scaffolds. In the second path, side chains intended to activate substrates noncovalently either through H-bonding or cation-π-interactions will be explored. The third path will focus on adding bipyridine or terpyridine units that will be used for complexation with nickel and subsequently α-arylation of aldehydes. In the second goal, the team will seek to harness the modularity of foldamer scaffolds to allow three functional groups to work in coordination to promote a single transformation. This project seeks to enable the development of new catalysts that are inspired by the structural diversity of enzymes. The ability to precisely control the location of multiple reactive sites within foldamers could additionally provide exciting opportunities of using these enzyme mimics for synergistic catalysis.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.