De Novo Asymmetric Synthesis of Natural and Unnatural Oligosaccharide Motifs

在化学系（CHE）化学合成计划（SYN）的支持下，东北大学的乔治·奥多赫蒂教授和他的研究团队将致力于开发构建复杂寡糖结构基序的新方法和策略。在生物聚合物/低聚物中，包括蛋白质、DNA（2 '-脱氧核糖核酸）和RNA（核糖核酸），寡糖在其有限的合成可及性方面是独特的。具体地，现代合成化学已经建立了用于快速组装具有天然和非天然亚基的肽和核苷酸寡聚体的方法。相比之下，将碳水化合物组装成低聚基序的能力受限于实际制备全范围的可接近的区域和立体异构体结构的能力。这些合成限制抑制了寡糖基序作为新材料和治疗剂的研究和使用。该项目的更广泛的影响是（i）可推广的寡糖合成方法将带来的长期科学效益，以及（ii）这些研究对不同学生的培训。除了创造新的寡糖结构和新的组装方法外，这些项目还将为学生提供多步复杂分子合成的概念和技术培训。接受这些挑战的学生来自不同的背景和经验水平。这个多样化的学生群体（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，其中大多数人都找到了工作。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以及由此产生的天然和非天然寡糖基序。与大多数寡糖合成方法不同，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，将追求立体选择性合成碳水化合物单体的不对称催化。其次是开发不足的方法;即过渡金属介导的糖基化或环化将用于区域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（假）寡糖基序。使用不对称催化合成单体允许一定程度的立体化学灵活性的方法，更传统的方法不容易提供。糖基化反应组装含有碳水化合物单体的双键，这也产生一定程度的结构灵活性，并允许最小限度地使用醇保护。避免使用保护基团可以显著减少化学废物的产生。总的来说，该项目旨在从根本上改变寡糖合成，进而改变碳水化合物化学在化学生物学中的应用，并最终改变药物化学。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。

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.