Bifunctional foldamer catalysis

在化学系大分子、超分子和纳米化学项目的资助下，塞缪尔·H·威斯康星大学麦迪逊分校的盖尔曼正在开发新型的蛋白质样分子。 这项基础研究受到了生物学的启发。 所有生物体都含有序列特异性寡聚体和聚合物，它们可以折叠成特定的形状，这些形状使复杂的功能成为可能。 许多这些折叠的分子，如酶，在人体细胞内进行关键的化学转化。 盖尔曼的实验室创造了非天然的低聚物，或“折叠体”，采用离散的形状和催化化学反应。 使用β-和γ-氨基酸作为蛋白质中发现的天然α-氨基酸的替代构建块来制备折叠体。 天然蛋白质的折叠导致关键亚基被排列成精确的三维阵列，这对于与其他分子结合和催化化学反应至关重要。 这项研究的一个中心目标是开发具有蛋白质样结合和/或催化特性的合成折叠体。 这些人工折叠体最终可能在特定功能方面超过蛋白质。 与该奖项相关的基础研究可能最终导致在分子水平上开发新型药物分子或新型制造能力。 这项工作为跨学科研究提供了很好的培训。 它还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。 盖尔曼和他的研究团队参加了“化学机会”计划，旨在向本科生介绍威斯康星大学麦迪逊分校的研究生水平的机会。这项研究的重点是分子设计方面的前沿挑战，具体目标是开发促进重要化学转化的新型折叠体催化剂。 折叠体支架含有β-和/或γ-氨基酸残基，并采用多样化和稳定的螺旋二级结构。 特别强调的是放在双功能催化羟醛反应，产生大环。 通过碳-碳键形成合成大分子环是困难的，因为熵垒使得分子间反应能够与环化竞争。 烯烃复分解反应是一种广泛应用的合成大环化合物的有效方法，本研究旨在开发基于折叠体催化的互补方法。 其他正在探索的环化反应包括醛与烯酸酯的共轭加成。 所追求的来自催化过程的新产品包括一类洗涤剂，其中疏水部分是大环烷基单元，而不是更熟悉的线性烷基单元。 这些新型去污剂的行为可以提供结构-性质关系的基本见解，这一努力可能会产生有用的工具，膜蛋白的研究。 该奖项反映了NSF的法定使命，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 funding from the Macromolecular, Supramolecular and Nanochemistry Program of the Chemistry Division, Professor Samuel H. Gellman of the University of Wisconsin-Madison is developing new types of protein-like molecules. This fundamental research is biologically inspired. All organisms contain sequence-specific oligomers and polymers that fold into particular shapes, and these shapes enable complex functions. Many of these folded molecules, such as enzymes, carry out crucial chemical transformations within the cells in the human body. Gellman's laboratory creates unnatural oligomers, or "foldamers", that adopt discrete shapes and catalyze chemical reactions. The foldamers are prepared using beta- and gamma-amino acids as alternative building blocks to the natural alpha-amino acids found in proteins. The folding of natural proteins causes key subunits to be arranged into the precise three-dimensional arrays that are essential for binding to other molecules and catalyzing chemical reactions. A central aim of this research is to develop synthetic foldamers that exhibit protein-like binding and/or catalytic properties. These artificial foldamers might ultimately surpass proteins in terms of specific functions. The basic research associated with this award could ultimately lead to development of new types of drug molecules or new types of manufacturing capabilities at the molecular level. This work provides excellent training in interdisciplinary research. It also enables young scholars to undertake productive careers in academics, industry or other settings. Gellman and his research team participate in the "Chemistry Opportunities" program intended to introduce undergraduate students to graduate-level opportunities at the University of Wisconsin-Madison. This research focuses on cutting-edge challenges in terms of molecular design, with the specific goal of developing new types of foldamer catalysts that facilitate important chemical transformations. The foldamer scaffolds contain beta- and/or gamma-amino acid residues and adopt diverse and stable helical secondary structures. Particular emphasis is placed on bifunctional catalysis of aldol reactions that produce macrocycles. Synthesizing large molecular rings via carbon-carbon bond formation is difficult because of entropic barriers that enable intermolecular reactions to compete with cyclization. Olefin metathesis has been a widely used and powerful method for macrocycle formation, and this research aims to develop complementary methods based on foldamer catalysis. Other cyclization reactions under exploration include conjugate additions of aldehydes to enoate esters. Novel products from the catalytic processes under pursuit include a class of detergents in which the hydrophobic portion is the macrocyclic alkyl unit, rather than a more familiar linear alkyl unit. The behavior of these novel detergents could provide fundamental insights on structure-property relationships, and this effort may generate useful tools for membrane protein studies. Transformative chemistry associated with this research offers opportunities for invention in terms of basic research and practical development.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.