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.

项目概要/摘要 该提案描述了利用基本化学性质来改变试剂的反应性 生物医学上重要的化合物的合成 碳水化合物在生物系统中的作用是不可能的。 被夸大了，并且对科学研究非常感兴趣。糖基化的稳健、实用和通用方法。 具有可预测立体选择性的反应将有助于进一步研究糖在生物化学中的作用 尽管最近取得了进展，但聚糖合成仍然是一项具有挑战性的工作，主要是为人类保留的。 糖化学领域的专家们认为，2-脱氧-β-糖苷的通用、选择性合成仍然难以实现。 氢键供体催化剂将用于改变 2-脱氧-α-磷酸供体的固有反应性 2-脱氧-β-糖苷 (K99) 的选择性合成 该合成依赖于磷酸盐的原位生成。 酯糖基供体，以及鉴定定制的有机催化剂以促进立体特异性 通过同时激活亲电子试剂（供体）和亲核试剂（受体）进行糖基化。 开发合成 2-脱氧-β-糖苷的通用方法 1) 为以下问题提供了解决方案 缺乏 C2 的糖的糖基化通常通过嵌合辅助用作导向基团，2) 能够进一步研究它们在生物化学和医学中的作用，并且3）提供了一种替代方案 生物活性天然产物的合成策略。 其次，C-S键的化学性质将用于合成新型供体-受体 Stenhouse 加合物，DASA (R00) 尽管 Stenhouse 加合物于 2014 年推出，但它们用于药物。 传输、动态相转移、聚合物、液晶、波长选择性光开关和 尽管 DASA 的应用前景广阔，但目前仍受到其结构的限制。 目前，DASA 系统中通常只使用胺供体和两个受体。 硫、磷化氢、氧或其他杂原子供体将扩大应用范围并提供更多 已知应用的有效化合物的合成依赖于使用 2-噻吩甲醛，一种 经济的起始材料，可避免使用糠醛 2- 时面临的反应性问题。 噻吩甲醛具有较弱且较长的 C-S 键，而不是负责产生化学反应的 C-O 键。 使用糠醛衍生物时，无法将其他供体功能纳入 DASA 中； 碳原子上的电子密度较小，使其成为冷凝时开环的完美基材 如果C-S键不够弱，可极化硫将被亲硫剂激活。 合成新型 Stenhouse 加合物 1) 提供了额外的 DASA 来探索列出的应用。 如上所述，2) 能够进一步研究这些新型光电开关的化学特性，3) 提供了 开发其他应用程序的机会。