Atsuko Awata

Catalytic asymmetric exo'-selective [3+2] cycloaddition for constructing stereochemically diversified spiro[pyrrolidin-3,3'-oxindole]s.

of spirotryprostatin A led to a structure-based design of potent inhibitors by regulating the interaction between tumor suppressor p53 and E3 ubiquitin ligase MDM2. The fascinating chiral spiro[pyrrolidin-3,3’-oxindole] scaffolds have been conventionally constructed via [3+2] cycloaddition of enantiomerically enriched substrates of 2-oxoindolin-3-ylidene derivatives and azomethine ylides. In 2009, Gong and co-workers reported the first catalytic asymmetric synthesis of spiro[pyrrolidin-3,3’-oxindole] via threecomponent [3+2] cycloaddition by using a chiral Brønsted acid catalyst. Waldman and co-workers established the exo-selective [3+2] cycloaddition of methyleneindolinone and iminoester catalyzed by the N,P-ferrocenyl ligand and [CuPF6ACHTUNGTRENNUNG(CH3CN)4] complex. Recently, Wang and co-workers have also reported the 4,4’,6,6’-tetrakis-trifluoromethylbiphenyl-2,2-diaminophosphonite (TF–BiphamPhos)–Ag catalyzed exo-selective [3+2] cycloaddition. The pioneering works on the exo-selective [3+2] cycloadditions have been successfully applied not only for synthesizing natural products, but also for screening a new generation of biologically active compounds. Because the biological activity of optically active compounds strictly correlates with the stereochemistry of the compounds, which controls the position and direction of functional groups, a flexible and diversified methodology for accessing various combinations of chiral networks is highly desirable, but has yet to be established. A program to provide a flexible route for such stereochemically diversified spiro[pyrrolidin-3,3’-oxindole]s is categorized into four groups as shown in Scheme 1. When

Catalytic asymmetric Friedel-Crafts/protonation of nitroalkenes and N-heteroaromatics.

The catalytic asymmetric Friedel-Crafts/protonation of indoles and pyrroles with α-substituted nitroalkenes to give the corresponding adducts in a highly anti-selective manner was achieved by an imidazoline-aminophenol (L2)-Cu complex. The anti-adducts could be successfully transformed to biochemically important α-substituted β-heteroarylalkylamines.

Catalytic Asymmetric Synthesis of Chiral 2-Vinylindole Scaffolds by Friedel–Crafts Reaction

A chiral bis(imidazolidine)pyridine (PyBidine)-Ni(OTf)2 complex smoothly catalyzed an asymmetric Friedel-Crafts reaction of 2-vinylindoles with nitroalkenes to give chiral indoles in a highly enantioselective manner while maintaining the 2-vinyl functionality. The chiral 2-vinylindoles offer unique chiral scaffolds for diverse transformations.

A novel indole compound, AWT-489, inhibits prostaglandin D2-induced CD55 expression by acting on DP prostanoid receptors as an antagonist in LS174T human colon cancer cells.

Indoles are composed of a common core structure, the indole ring, and are widely used as pharmaceuticals and their precursors. In this study, a newly composed relatively small indole compound, AWT-489 was examined to find a novel specific antagonist for DP receptors; the cognate receptors for prostaglandin D2 (PGD2), to prevent colon cancer malignancy. Here we showed that AWT-489 antagonized DP receptor-mediated cyclic AMP formation, and expression of CD55, an inhibitor of the complement system that correlates with poor survival in patients with colorectal cancer, in LS174T human colon cancer cells. Interestingly, unlike a popular indole compound, indomethacin, AWT-489 did not act on the cyclooxygenases as a non-steroidal anti-inflammatory drug. Moreover, AWT-489 exhibited a better inhibitory effect than that of the well-used DP receptor antagonist, BWA868C when a dose close to the physiological concentration of PGD2 was used. These results suggest that AWT-489 can act as a novel human DP receptor antagonist to reduce the expression of CD55 in LS174T human colon cancer cells. We believe that AWT-489 has potential as a lead compound for designing a new DP receptor antagonist that may help improve PGD2-related diseases, especially colon cancer in the near future.