De Novo Asymmetric Synthesis of Natural and Unnatural Oligosaccharide Motifs

在东北大学化学系化学合成项目（SYN）的支持下，George O 'Doherty教授和他的研究团队将致力于开发新的方法和策略来构建复杂的低聚糖结构基序。在包括蛋白质、DNA（2'-脱氧核糖核酸）和RNA（核糖核酸）在内的生物聚合物/低聚物中，低聚糖的独特之处在于其有限的合成可及性。具体来说，现代合成化学已经建立了快速组装天然和非天然亚基的肽和核苷酸低聚物的方法。相比之下，将碳水化合物组装成低聚基序的能力在实际制备全范围可接近的区域和立体异构体结构的能力方面受到限制。这些合成限制抑制了低聚糖基序作为新材料和新疗法的研究和使用。这个项目更广泛的影响是：(1)可推广的低聚糖合成方法将给科学带来的长期利益；(2)这些研究为不同的学生群体带来的培训。除了创造新的低聚糖结构和新的组装方法外，这些项目还将为学生提供多步骤复杂分子合成的概念和技术方面的培训。接受这些挑战的学生来自不同的背景和经验水平。这个多元化的学生群体（高中，本科，研究生和博士后）主要由来自美国和世界各地的女性和代表性不足的学生组成。这些学生获得的有机合成技能受到生物技术、制药和材料科学行业的高度重视，他们中的大多数都在这些行业找到了工作。该项目旨在开发新的合成方法，以获得更广泛的碳水化合物单体和由此产生的天然和非天然低聚糖基序。与大多数低聚糖合成方法不同，这种独特的合成方法严重依赖于过渡金属催化的使用。首先，研究了碳水化合物单体立体选择性合成的不对称催化。然后是未被充分利用的方法；也就是说，过渡金属介导的糖基化或环化将用于区域选择性和立体选择性地将碳水化合物单体或其碳环类似物组装成（伪）低聚糖基序。使用不对称催化合成单体，使得这种方法具有一定程度的立体化学灵活性，这是传统方法所不能提供的。糖基化反应组装了含有碳水化合物单体的双键，这也产生了一定程度的结构灵活性，并允许最小限度地使用醇保护。避免保护群体可以显著减少化学废物的产生。总体而言，该项目旨在从根本上改变低聚糖的合成，进而改变碳水化合物化学在化学生物学，最终药物化学中的实际问题中的应用。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 Chemical Synthesis Program (SYN) in the Division of Chemistry (CHE), Professor George O’Doherty and his research team at Northeastern University will work to develop new methods and strategies for the construction of complex, oligosaccharide structural motifs. Of the bio-polymers/oligomers, including proteins, DNA (2'-deoxyribonucleic acid) and RNA (ribonucleic acid), oligosaccharides stand unique in terms of their limited synthetic accessibility. Specifically, modern synthetic chemistry has established methods for the rapid assembly of peptide and nucleotide oligomers with both natural and unnatural subunits. In comparison, the ability to assemble carbohydrates into oligomeric motifs is limited in the ability to practically prepare the full range of accessible regio- and stereo-isomeric structures. These synthetic limitations inhibit the study and use of oligosaccharide motifs as new materials and therapeutics. The broader impacts of this project are to (i) the long-term benefits to science that generalizable oligosaccharide synthesis methods will bring and (ii) the training that these studies engender to a diverse set of students. In addition to the creation of new oligosaccharide structures and new methods for their assembly, these projects will give students training in the concepts and techniques of multi-step complex molecule synthesis. The students who take up these challenges come from a range of backgrounds and experience levels. This diverse group of students (high school, undergraduate, graduate and postdoctoral) is significantly made up of women and under-represented students from the US and around the world. The skills in organic synthesis that these students gain are highly valued by the biotechnology, pharmaceutical and material science industries, where most of them find employment. This project aims to develop new synthetic methods to access a wider range of carbohydrate monomers and the resulting natural and unnatural oligosaccharide motifs. This unique synthetic approach heavily relies on the use of transition metal catalysis unlike most oligosaccharide synthesis methods. First asymmetric catalysis for the stereoselective synthesis of the carbohydrate monomers will be pursued. Then an underexploited approach; namely, transition metal-mediated glycosylation or cyclitolization will be used to regio- and stereo-selectively assemble the carbohydrate monomers, or their carbocyclic analogues, into (pseudo)oligosaccharide motifs. The use of asymmetric catalysis for the synthesis of the monomers allows a degree of stereochemical flexibility to the approach that more traditional methods do not readily offer. The glycosylation reaction assembles double bonds containing carbohydrate monomers, which also engenders a degree of structural flexibility as well as allows for the minimal use of alcohol protections. Avoiding protecting groups can significantly reduce the amount of chemical waste generated. Overall, the project aims to fundamentally change oligosaccharide synthesis and in turn also change the application of carbohydrate chemistry to real-world problems in chemical biology, and eventually, medicinal chemistry.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.