CAREER: Carbohydrate Synthesis with Anomeric Nucleophiles

美国国家科学基金会化学部的化学合成项目通过这一职业奖支持科罗拉多大学博尔德分校化学系Maciej Walczak教授的研究。Walczak教授和他的学生开发了制造碳水化合物的新方法。碳水化合物是最丰富的生物聚合物，参与体内的能量储存。它们还控制着体内的分子识别事件。本研究开发了多种合成生物活性糖苷和糖肽的方法。本研究可以全面研究碳水化合物在生物学中的作用，为制备高价值的生物化合物和药物制剂提供便利。该合成方法具体地使抗糖尿病药物和抗肿瘤抗生素的制备成为可能。沃尔扎克教授的小组在教育和培训来自科学领域代表性不足的群体的学生方面处于有利地位。外联活动的重点是提高当地社区的科学意识，特别是通过高中教育和公开演讲。该教育项目整合了院系和大学层面的努力，以创建一个在化学和生物学界面工作的研究人员的协作社区。本研究开发了多种合成生物活性糖的新方法，主要是糖苷和糖肽。大多数已知的合成糖的方法都集中在用电负性元素取代头异构位置的底物上。这种方法有一些局限性，如底物依赖性，需要保护基团操作，以及与游离醇基团不相容。NSF CAREER奖的中心假设是构型稳定的亲核试剂在过渡金属催化条件下参与立体定向反应，形成具有高选择性的碳-碳和碳-氮键。这些部分与底物和催化剂的性质无关。利用这些新的概念基础，追求三个具体目标：(a)发展异头硼酸的交叉偶联反应，(b)实现合成碳糖苷的新化学方法，以及(c)开发合成氮连接糖蛋白的新方法。这些目标的成功实现产生了新的umpolung方法，消除了以前方法固有的关键问题。该合成方法还可以在标准化和用户友好的条件下制备抗糖尿病药物、抗肿瘤抗生素、糖蛋白和糖肽类药物。该研究项目还与正在进行的教育和推广活动密切相关。正在开发和实施一门以混合学习为特色，辅以随机试验的本科课程，以改进本科教学方法。外展活动的重点是辅导高中生。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 this CAREER award, the Chemical Synthesis Program of the NSF Chemistry Division supports the research of Professor Maciej Walczak in the Department of Chemistry at the University of Colorado in Boulder. Professor Walczak and his students develop new methods to make carbohydrates. Carbohydrates, the most abundant biopolymers, are involved in energy storage in the body. They also control molecular recognition events in the body. This research develops versatile methods for the synthesis of bioactive glycosides and glycopeptides. This research enables comprehensive studies on the function of carbohydrates in biology, and facilitates the preparation of high-value biological compounds and pharmaceutical agents. The synthetic approaches specifically enable the preparation of anti-diabetic drugs and anti-tumor antibiotics. Professor Walczak's group is well positioned to educate and train students from groups that are underrepresented in science. Outreach activities focus on improving science awareness in the local communities, specifically through education at the high school level and public presentations. The education program integrates efforts at the department and university levels to create a collaborative community of researchers working at the interface of chemistry and biology.This research develops versatile new methodologies for the synthesis of bioactive saccharides, primarily glycosides and glycopeptides. A majority of known methods to synthesize saccharides focus on substrates in which the anomeric position is substituted with an electronegative element. This approach bears several limitations such as substrate dependence, the need for protective group manipulations, and incompatibility with free alcohol groups. The central hypothesis of this NSF CAREER award is that configurationally stable anomeric nucleophiles are engaged in stereospecific (stereoretentive) reactions under transition metal-catalyzed conditions, forming carbon-carbon and carbon-nitrogen bonds with high selectivities. These moieties are independent from the nature of the substrates and catalysts. Capitalizing on these new conceptual foundations, three specific aims are pursued: (a) the development of cross-coupling reactions of anomeric boronic acids, (b) the implementation of new chemical methods for the synthesis of carbon-glycosides, and (c) the development of new methods in the synthesis of nitrogen-linked glycoproteins. Successful realization of these aims yields novel umpolung methods that eliminate the critical problems inherent to the previous approaches. The synthetic approaches also enable the preparation of anti-diabetic drugs, anti-tumor antibiotics, glycoproteins, and glycopeptides under standardized and user-friendly conditions. The research program is also intimately connected with ongoing educational and outreach activities. An undergraduate course featuring blended learning supplemented by randomized trial to improve undergraduate pedagogy is being developed and implemented. The outreach activities focus on mentoring high-school students.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.