| Description |
ortho-Quinone methides (o-QMs) are highly reactive intermediates with various applications in chemical and biological sciences. In the last decade, chemists have utilized o-QM reactivity to develop numerous synthetic transformations that provide access to biologically relevant scaffolds, such as chromanes. However, enantioselective functionalization of o-QM is still a challenge. Presented herein are functionalization reactions of o-QMs with a chiral Pd-catalyst to provide biologically relevant chromane and bis-arylmethane scaffolds in excellent enantioselectivity. These studies are followed by development of hydrofunctionalization of vinyl phenols and vinyl indoles to provide the corresponding bis-arylmethanes. In the first study, a unique approach to alkene difunctionalization was taken based on a mechanistic hypothesis of a quinone methide intermediate in a related reaction. Substrates containing an alkene adjacent to an ortho-phenol and a tethered nucleophile were prepared, allowing for the regioselective addition of two distinct nucleophiles. The reaction was applied to the dialkoxylation of alkenes, resulting in the enantioselective formation of heterocyclic compounds bearing two adjacent chiral centers. In the second study, a Pd-catalyzed enantioselective reaction of indoles with o-QMs was developed, using a similar strategy as above, to provide bis-arylmethanes. Since many biologically active compounds contain bis-arylmethane functionality, several of the newly synthesized compounds were screened against breast cancer cell lines. Two of newly synthesized bis-arylmethanes, 69 and 72, demonstrated micromolar anti-cancer activity against breast cancer cell lines with different phenotypes. Inspired by promising biological activity of bis-arylmethanes, a unique hydrofunctionalization reaction of vinyl phenol with heteroaromatics was developed to provide analogous structures. The key development in this process is use of alkyl chloride as a sacrificial hydride source to provide the requisite Pd-hydride. Finally, acid-catalyzed hydrofunctionalization of vinyl indoles with heteroaromatics was developed. This process provides unsymmetrical bisindolylmethanes in high yields. The biological studies of newly synthesized compounds demonstrated anti-cancer activity against breast cancer cell lines. One of the newly synthesized compound, 149, demonstrated excellent deferential activity between wildtype breast cell lines and cancerous cell lines. |
