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: 10531719
• 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/10531719
• 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; Ursidae Family; adduct; biological systems; catalyst; chemical property; electron density; glycosylation; inorganic phosphate; interest; liquid crystal; novel; phosphate ester; physical property; programs; 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.

项目总结/摘要 该提案描述了使用基本化学性质来改变试剂的反应性， 生物医学上重要化合物的合成。碳水化合物在生物系统中的作用不能被忽视。 被夸大了，对科学研究有很大的兴趣。用于糖基化的稳健、实用和通用方法 具有可预测的立体选择性的反应将使进一步研究糖在生物化学中的作用成为可能 和医药尽管最近的进展，聚糖合成仍然是一个具有挑战性的奋进，主要是保留给 糖化学领域的专家，并且2-脱氧-β-糖苷的一般选择性合成仍然是难以捉摸的。 氢键供体催化剂将用于改变2-脱氧-α-磷酸供体对磷酸的固有反应性。 2-脱氧-β-糖苷（K99）的选择性合成。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 通过同时激活亲电体（供体）和亲核体（受体）来进行糖基化。 开发合成2-脱氧-β-糖苷的通用方法1）为合成2-脱氧-β-糖苷提供了解决方案。 缺乏C2官能团的糖的糖基化，其通常经由邻位辅助用作导向基团，2） 能够进一步研究它们在生物化学和医学中的作用，3）提供了一种替代方案 生物活性天然产物的合成策略。 第二，利用C-S键的化学性质合成新型的给体-受体 Stenhouse加合物，DASA（R 00）。虽然Stenhouse加合物是在2014年引入的，但它们被用于药物 传递、动态相转移、聚合物、液晶、波长选择性光开关，以及 化学传感应用。尽管它们有很好的应用前景，但DASA目前受到其结构的限制。 多样性目前，在DASA体系中通常仅使用胺供体和两种受体。新型加合物， 硫、膦、氧或其它杂原子供体将扩大应用范围，并提供更多的 用于已知应用的有效化合物。该合成依赖于使用2-噻吩甲醛， 经济的原料，将避免使用糠醛时面临的反应性问题。2- 噻吩甲醛具有较弱且较长的C-S键，代替负责 当使用糠醛时，不能在DASA中引入其它供体官能团;噻吩衍生物还携带 碳原子上的电子密度更小，使其成为在缩合时开环的完美基质， 受体分子如果C-S键不够弱，则可极化硫将被亲硫试剂活化。 刘易斯酸。合成新型Stenhouse加合物1）提供额外的DASA以探索列出的应用 2）能够进一步研究这些新型光开关的化学性质，以及3）提供了一种 开发更多应用的机会。