Strategic Molecular Activations for the Selective Synthesis of 2-Deoxy-Beta-Glycosides, and for the Synthesis of Novel Donor-Acceptor Stenhouse Adducts

用于选择性合成 2-脱氧-β-糖苷和合成新型供体-受体 Stenhouse 加合物的战略分子激活

• 批准号: 10573277
• 负责人: Elias Picazo
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF SOUTHERN CALIFORNIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10573277
• 关键词: Acids; Address; Amines; Biochemistry; Carbohydrates; Carbon; Chemistry; Complement; Drug Delivery Systems; Foundations; Generations; Glycosides; Hydrogen Bonding; In Situ; Medical; Medicine; Methods; Molecular; Molecular Conformation; Natural Products; Oxygen; Phase; Phosphines; Phosphorus; Polymers; Polysaccharides; Property; Reaction; Reagent; Research; Role; Science; Specialist; Structure; Sulfur; Surface; System; Thiophenes; Training; adduct; biological systems; catalyst; chemical property; electron density; glycosylation; inorganic phosphate; interest; liquid crystal; novel; phosphate ester; physical property; programs; restraint; scaffold; sugar

Project Summary/Abstract This proposal describes the use of fundamental chemical properties to alter the reactivity of reagents for the synthesis of biomedically important compounds. The role of carbohydrates in biological systems cannot be overstated and is of great interest to scientific research. Robust, practical, and general methods for glycosylation reactions with predictable stereoselectivity will enable further research in the role of sugars in biological chemistry and medicine. Despite recent advances, glycan synthesis remains a challenging endeavor largely reserved for specialists in sugar chemistry, and a general, selective synthesis of 2-deoxy-β-glycosides remains elusive. Hydrogen-bond-donor catalysts will be used to alter the innate reactivity of 2-deoxy-a-phosphate donors for the selective synthesis of 2-deoxy-β-glycosides (K99). The synthesis relies on the in situ generation of a phosphate ester glycosyl donor, and on the identification of a tailored organocatalyst to promote stereospecific glycosylations by simultaneously activating the electrophile (the donor) and the nucleophile (the acceptor). Developing a general method for the synthesis of 2-deoxy-β-glycosides 1) provides a solution for the glycosylation of sugars lacking the C2 functionality often used as a directing group via anchimeric assistance, 2) enables further research on their role in biological chemistry and medicine, and 3) provides an alternative strategy for the synthesis of biologically active natural products. Secondly, the chemical properties of C–S bonds will be used for the synthesis of novel donor-acceptor Stenhouse adducts, DASAs (R00). Though Stenhouse adducts were introduced in 2014, they are used in drug delivery, dynamic phase transfer, polymers, liquid crystals, wavelength-selective photoswitching, and chemosensing applications. Despite their promising applications, DASAs are currently limited by their structural diversity. Only amine donors and two acceptors are generally used in DASA systems today. Novel adducts with sulfur, phosphine, oxygen, or other heteroatom donors will expand the pool of applications and provide more efficient compounds for known applications. The synthesis relies on using 2-thiophenecarboxaldehyde, an economical starting material that will circumvent reactivity problems faced when using furfural. 2- Thiophenecarboxaldehyde bears a weaker and longer C–S bond in place of the C–O bond responsible for the inability to incorporate other donor functionality in DASAs when using furfural; thiophene derivatives also carry less electron density on the carbon atoms, making it a perfect substrate for ring opening upon condensing an acceptor molecule. If the C–S bond is not sufficiently weak, the polarizable sulfur will be activated using thiophilic Lewis acids. Synthesizing novel Stenhouse adducts 1) provides additional DASAs to explore applications listed above, 2) enables further research on the chemical properties of these new photoswitches, and 3) provides an opportunity to develop additional applications.

项目摘要/摘要 该建议描述了使用基本化学特性来改变试剂的反应性 生物医学重要化合物的合成。碳水合物在生物系统中的作用不能是 夸大其词，对科学研究非常感兴趣。糖基化的强大，实用和一般方法 具有可预测的立体选择性的反应将使糖在生物化学中的作用进一步研究 和医学。尽管最近进步，但是聚糖合成仍然是一项挑战，主要保留了 糖化学专家以及2-脱氧 - 糖苷的一般选择性合成仍然难以捉摸。 氢键含量催化剂将用于改变2-磷酸盐供体的先天反应性 2-脱氧-β-糖苷的选择性合成（K99）。合成依赖于磷酸盐的原位产生 酯糖基供体，以及识别量身定​​制的有机催化剂以促进立体特异 通过简单地激活亲电的糖基化（供体）和核腓杆菌（受体）。 开发一种合成2-脱氧-β-糖苷的一般方法1）为该解决方案提供了解决方案 缺乏C2功能的糖糖基通常通过锚固辅助用作指导组，2） 可以进一步研究其在生物化学和医学中的作用，3）提供了替代方案 合成生物活性天然产物的策略。 其次，C – S键的化学特性将用于合成新型供体知识者 Stenhouse加合物，Dasas（R00）。尽管2014年引入了Stenhouse加合物，但它们用于毒品 输送，动态相转移，聚合物，液晶，波长选择性照片处理，并且 化学传感应用。尽管有承诺的申请，但DASA目前受到其结构的限制 多样性。如今，DASA系统通常仅使用胺捐献者和两个受体。带有新颖的加合物 硫，磷酸，氧或其他杂原子供体将扩大应用的池并提供更多 已知应用的有效化合物。合成依赖于使用2-硫代苯甲甲醛，一个 经济的起始材料将避免使用呋喃时面临的反应性问题。 2- 硫代苯甲甲醛代替了C – O键较弱且更长的C键键 使用Furfural时，无法在DASA中纳入其他供体功能；噻吩衍生物也携带 碳原子上的电子密度较小，使其成为凝结后环开口的理想基板 受体分子。如果C – S键不够弱，则将使用硫代硫酸激活极化的硫 路易斯酸。合成新颖的Stenhouse Addcts 1）提供了其他DASA，以探索列出的应用程序 以上，2）对这些新照片开关的化学特性进行进一步研究，3）提供了 开发其他应用程序的机会。