Synthesis of Bisanthraquinone Natural Product and BINOL-type Chiral Ligands

双蒽醌天然产物和联醇型手性配体的合成

• 批准号: 7915021
• 负责人: Erin Eileen Podlesny
• 金额: $ 4.14万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7915021
• 关键词: Acetals; Affect; Alder plant; Antioxidants; BINOL; Biocompatible Materials; Biological; Biological Factors; Catalysis; Chemistry; Coupling; Development; Diabetes Mellitus; Disease; Effectiveness; Electrons; Generations; Goals; Health; Hepatitis; High Pressure Liquid Chromatography; Ligands; Mental Depression; Methods; Naphthols; Pharmaceutical Chemistry; Pharmacologic Substance; Property; Public Health; Quinones; Reaction; Reporting; Research; Skin; Structure; Therapeutic Agents; Ultraviolet Rays; analog; cancer therapy; cell growth; enantiomer; ketene; neoplastic cell; oxidation; physical property; public health relevance; skyrin

DESCRIPTION (provided by applicant): This project will result in total synthesis of a group of axially chiral bisanthraquinone natural products that has not been synthesized previously, providing material for biological study. The reported biological activity and physical properties of some of these compounds affects a variety of public health issues including treatment of cancer (suppression of tumor cell growth),7 diabetes,8 hepatitis,9 and depression.10 Also, antioxidant properties have been reported, which may have potential in protecting skin against the effects of UV radiation.12 Still, a great deal of information is lacking for the activity of many of these bisanthraquinones, citing a need for more biological studies. An efficient synthesis of these molecules is central to achieving these goals. Specifically, the generation of the compounds will be achieved via a concerted synthesis that diverges from the same chiral bisnaphthoquinone intermediate (1a). This versatile bisnapththoquinone intermediate will be synthesized from a 2-naphthol via an enatioselective oxidative biaryl coupling reaction, followed by oxidation to 1. Tandem Diels-Alder/aromatization reactions between 1a and various vinyl ketene acetals (2) will provide the bisanthraquinone structure and subsequent transformations will afford natural products (3-7). In addition, a new class of BINOL-type chiral ligands (8a-b) will be generated from a simpler bisnaphthoquinone precursor (1b). The synthesis of these ligands is important because they could positively impact asymmetric catalysis. Catalytic asymmetric synthesis is important to scientific research because it provides an important means of structural control in synthesis. The synthesis of a specific enantiomer or diastereomer is important in both pharmaceutical and materials chemistry because enantiomers of a particular therapeutic agent may have dissimilar biological activity or materials may have different properties. Following analysis of the stability of these molecules via NMR and HPLC, assessment of their effectiveness in asymmetric catalysis will be explored. Specifically these BINOL analogs will be compared to BINOL, H8- BINOL, perfluoro-BINOL and other electron deficient BINOLs via comparison of yield and enantiomeric excess in a variety of known reactions. Other more hindered derivatives (extended from the quinone moiety) will also be synthesized and analyzed. Bisnaphthoquinone natural products BINOL analogs OH O OH R2 R1 OR3 O O R1 OR3 R2 OH O OH 3 R1 = Me, R2 = R3 = H skyrin 4 R1 = OMe, R2 = R3 = H bislunatin 5 R1 = R2 = R3 = Me trachypone 6 R1 = OMe, R2 = Me, R3= H 7 R1 = R2 = R3 = H O R OTMS 2 OR4 CO2Me R1 O O OMe OMe CO2Me O R 1a R = OMe b R = H O R OH O O OH R O 8a R = H b R = Ar PUBLIC HEALTH RELEVANCE: The synthesis of bisanthraquinone natural products is relevant to public health because their biological activity may impact a variety of health issues, including treatment of cancer, diabetes, hepatitis, depression, and use as an antioxidant. An efficient synthesis of these molecules is central to a complete analysis of their activity. In addition, a new class of chiral BINOL analogs may positively impact asymmetric catalysis, which is an important method in pharmaceutical chemistry and development of therapeutic agents for treatment of disease.

项目描述（申请人提供）：本项目将全合成一组以前未合成过的轴向手性双蒽醌类天然产物，为生物学研究提供材料。这些化合物的生物活性和物理性质影响了包括癌症治疗在内的各种公共卫生问题（抑制肿瘤细胞生长）、7糖尿病、8肝炎、9和抑郁症。10此外，据报道，抗氧化剂特性可能具有保护皮肤免受紫外线辐射影响的潜力。12尽管如此，许多这类双蒽醌的活性缺乏大量信息，理由是需要进行更多的生物学研究。这些分子的有效合成是实现这些目标的核心。具体地，化合物的产生将通过偏离相同手性双萘醌中间体（1a）的协同合成来实现。这种多用途的双萘醌中间体将由2-萘酚通过对映选择性氧化联芳基偶联反应合成，然后氧化成1。1a和各种乙烯基烯酮缩醛（2）之间的串联Diels-Alder/芳构化反应将提供双蒽醌结构，随后的转化将提供天然产物（3-7）。 此外，一类新的BINOL型手性配体（8a-b）将从更简单的双萘醌前体（1b）生成。这些配体的合成是重要的，因为它们可以积极影响不对称催化。催化不对称合成是合成中结构控制的重要手段，对科学研究具有重要意义。特定对映异构体或非对映异构体的合成在药物化学和材料化学中都是重要的，因为特定治疗剂的对映异构体可能具有不同的生物活性或材料可能具有不同的性质。在通过NMR和HPLC分析这些分子的稳定性之后，将探索它们在不对称催化中的有效性的评估。具体地，这些BINOL类似物将通过比较各种已知反应中的产率和对映体过量与BINOL、H8- BINOL、全氟-BINOL和其他缺电子BINOL进行比较。其他更多的受阻衍生物（从醌部分延伸）也将被合成和分析。双萘醌天然产物BINOL类似物OH O OH R2 R1 OR 3 O O R1 OR 3 R2 OH O OH 3 R1 = Me，R2 = R3 = H skyrin 4 R1 = OMe，R2 = R3 = H bislunatin 5 R1 = R2 = R3 = Me四氢吡喃酮6 R1 = OMe，R2 = Me，R3= H 7 R1 = R2 = R3 = H O R OTMS 2 OR4 CO2 Me R1 O O OMe OMe CO2 Me O R 1a R = OMe B b R = H O R OH O O OH R O 8a R = H B b R = Ar 公共卫生关系：双蒽醌天然产物的合成与公共卫生有关，因为它们的生物活性可能影响各种健康问题，包括治疗癌症，糖尿病，肝炎，抑郁症和用作抗氧化剂。这些分子的有效合成对于完整分析其活性至关重要。此外，一类新的手性BINOL类似物可以积极地影响不对称催化，这是药物化学和开发用于治疗疾病的治疗剂的重要方法。