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
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.
|Metz, Alison E; Podlesny, Erin E; Carroll, Patrick J et al. (2014) Axial chiral bisbenzophenazines: solid-state self-assembly via halide hydrogen bonds triggered by linear alkanes. J Am Chem Soc 136:10601-4|
|Podlesny, Erin E; Kozlowski, Marisa C (2013) Divergent approach to the bisanthraquinone natural products: total synthesis of (S)-bisoranjidiol and derivatives from binaphtho-para-quinones. J Org Chem 78:466-76|
|Podlesny, Erin E; Kozlowski, Marisa C (2012) Enantioselective total synthesis of (S)-bisoranjidiol, an axially chiral bisanthraquinone. Org Lett 14:1408-11|
|Podlesny, Erin E; Carroll, Patrick J; Kozlowski, Marisa C (2012) Selective oxidation of 8,8'-hydroxylated binaphthols to bis-spironaphthalenones or binaphtho-para- and binaphtho-ortho-quinones. Org Lett 14:4862-5|
|Podlesny, Erin E; Kozlowski, Marisa C (2012) Structural reassignment of a marine metabolite from a binaphthalenetetrol to a tetrabrominated diphenyl ether. J Nat Prod 75:1125-9|