Synthesis of Bisanthraquinone Natural Product and BINOL-type Chiral Ligands

项目描述（由申请人提供）：本项目将合成一组未被合成的轴手性双蒽醌类天然产物，为生物学研究提供材料。据报道，其中一些化合物的生物活性和物理特性影响到各种公共卫生问题，包括治疗癌症（抑制肿瘤细胞生长）、糖尿病、肝炎、9和抑郁症此外，据报道，其抗氧化性能可能有助于保护皮肤免受紫外线辐射的影响尽管如此，许多双蒽醌类药物的活性仍然缺乏大量的信息，理由是需要更多的生物学研究。这些分子的有效合成是实现这些目标的关键。具体地说，化合物的生成将通过从相同的手性双萘醌中间体发散的协同合成来实现（1a）。这种多功能双萘醌中间体将由2-萘酚通过对映选择性氧化联芳偶联反应合成，然后氧化为1。1a和各种乙烯基酮缩醛(2)之间的串联diel - alder /芳构化反应将产生双蒽醌结构，随后的转化将产生天然产物（3-7）。此外，一类新的binol型手性配体（8a-b）将由更简单的双萘醌前体（1b）生成。这些配体的合成是重要的，因为它们可以积极地影响不对称催化。催化不对称合成对科学研究具有重要意义，因为它为合成提供了结构控制的重要手段。特定对映体或非对映体的合成在药物化学和材料化学中都很重要，因为特定治疗剂的对映体可能具有不同的生物活性或材料可能具有不同的性质。在通过核磁共振和高效液相色谱分析这些分子的稳定性之后，将探讨它们在不对称催化中的有效性。具体来说，这些BINOL类似物将与BINOL、H8- BINOL、全氟BINOL和其他缺电子BINOL进行比较，通过比较各种已知反应的产率和对映体过剩。其他更受阻的衍生物（从醌部分延伸）也将被合成和分析。Bisnaphthoquinone天然产物BINOL类似物哦啊哦R2 R1 OR3 O O R1 OR3 R2哦啊哦3 R1 =我,R2 = R3 skyrin 4 R1 = = H, R2 = R3 = H R3 bislunatin 5 R1 R2 = = =我trachypone 6 R1 =, R2 =我,R3 R2 = H 7 R1 = = R3 = H O R移动2 4 CO2Me R1 O O渗出性中耳炎中耳炎CO2Me O R 1 R =一些b R = H O R噢O O R O 8 a R = H R =基于“增大化现实”技术

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.