Synthesis of Bisanthraquinone Natural Product and BINOL-type Chiral Ligands

该项目将实现一组尚未合成的轴向手性双蒽醌天然产物的全合成，为生物研究提供材料。据报道，其中一些化合物的生物活性和物理特性影响着各种公共卫生问题，包括治疗癌症(抑制肿瘤细胞生长)、糖尿病、肝炎、抑郁症。[10]此外，已有报道称，抗氧化特性可能具有保护皮肤免受紫外线辐射影响的潜力。[12]然而，许多双蒽醌类化合物的活性缺乏大量信息，因此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关键。具体地说，化合物的生成将通过偏离相同的手性双萘醌中间体(1a)的协同合成来实现。这种用途广泛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与各种乙烯基缩酮缩醛(2)之间的串联Diels-Alder/芳构化反应将得到双蒽醌结构，随后的转化将得到天然产物(3-7)。 此外，一类新的联苯二醇型手性配体(8a-b)将由较简单的双萘二酚前体(1b)生成。这些配体的合成很重要，因为它们可以对不对称催化产生积极的影响。催化不对称合成在科学研究中具有重要意义，因为它为合成提供了重要的结构控制手段。特定对映体或非对映异构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，或者材料可能具有不同的性质。在通过核磁共振和高效液相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。具体地说，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剩来与BINOL、H{8}-BINOL、全氟BINOL和其他电子缺乏BINOL进行比较。还将合成和分析其他更多受阻的衍生物(由苯醌部分延伸而来)。

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, H{8}- 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.