Enantioselective Intermolecular C–O Bond Formation in the Desymmetrization of Diarylmethines Employing a Guanidinylated Peptide-Based Catalyst

We report a series of enantioselective C–O bond cross-coupling reactions based on remote symmetry breaking processes in diarylmethine substrates. The key to the chemistry is multifunctional guanidinylated peptide-based ligands that allow highly selective, intermolecular Cu-catalyzed cross-coupling of phenolic nucleophiles. The scope of the process is explored, demonstrating efficiency for substrates with a range of electronic and steric perturbations to the nucleophile. Scope and limitations are also reported for variation of the diarylmethine. While the presence of an intervening <i>t</i>Bu group is found to be optimal for maximum enantioselectivity, several other substituents may also be present such that appreciable selectivity can be achieved, providing an uncommon level of scope for diarylmethine desymmetrizations. In addition, chemoselective reactions are possible when there are phenolic hydroxyl groups within substrates that contain a second reactive site, setting the stage for applications in diverse complex molecular settings

Design, Synthesis, and Biological Activity of Sulfonamide Analogues of Antofine and Cryptopleurine as Potent and Orally Active Antitumor Agents

Due to their profound antiproliferative activity and unique mode of action, phenanthro­indolizidine and phenanthro­quinolizidine alkaloids, represented by antofine and cryptopleurine, have attracted attention recently as potential therapeutic agents. We have designed, synthesized, and evaluated the methanesulfonamide analogues of these natural alkaloids with the hope of improving their druglikeness. The analogues showed enhanced growth inhibition of human cancer cells compared with the parent natural products. In particular, a methanesulfonamide analogue of cryptopleurine (<b>5b</b>) exhibited improved bioavailability and significant antitumor activity, which suggests that <b>5b</b> is a promising new anticancer agent. Our studies suggest that the inhibition of cancer cell growth by <b>5b</b> is associated with the induction of G0/G1 cell cycle arrest via nicotinamide <i>N</i>-methyltransferase-dependent JNK activation in Caki-1 renal cancer cells. In addition, compound <b>5b</b> significantly inhibited the migration and invasion of Caki-1 cancer cells by modulating the p38 MAPK signaling pathway