Access to Cyclic ß-Amino Acids by Amine-Catalyzed Enantioselective Addition of the γ-Carbon Atoms of α,ß-Unsaturated Imines to Enals.

Disclosed herein is a new catalytic approach for an efficient access to cyclic ß-amino acids widely found in bioactive small molecules and peptidic foldamers. Our method involves addition of the remote γ-carbon atoms of α,ß-unsaturated imines to enals by iminium organic catalysis. This highly chemo- and stereo-selective reaction affords cyclic ß-amino aldehydes that can be converted to amino acids bearing quaternary stereocenters with exceptional optical purities. Our study demonstrates the unique power of organic catalytic remote carbon reactions in rapid synthesis of functional molecules.

Carbene-Catalyzed Desymmetrization and Direct Construction of Arenes with All-Carbon Quaternary Chiral Center.

Multisubstituted arenes such as indanes with attached all-carbon quaternary centers are unique scaffolds in synthetic functional molecules and sophisticated natural products. A key challenge in preparing such molecules lies in the enantioselective installation of the quaternary carbon centers. Conventional methods in this direction include asymmetric substitution reactions and substrate-controlled cyclization reactions. These reactions lead to poor stereoselectivities and/or require long and tedious synthetic steps. Disclosed here is a one-step organic catalytic strategy for enantioselective access to this class of molecules. The reaction involves an N-heterocyclic carbene catalyzed process for direct benzene construction, indane formation, remote-carbon desymmetrization, and excellent chirality control. This approach will enable the concise synthesis of arene-containing molecules, including those with complex structures and challenging chiral centers.

Access to All-Carbon Spirocycles through a Carbene and Thiourea Cocatalytic Desymmetrization Cascade Reaction.

A new catalytic approach for rapid asymmetric access to spirocycles is disclosed. The reaction involves a carbene- and thiourea-cocatalyzed desymmetrization process with the simultaneous installation of a spirocyclic core. The use of a thiourea cocatalyst is critical to turn on this reaction, as no product was formed in the absence of a thiourea. Our study constitutes the first success in the carbene-catalyzed enantioselective synthesis of all-carbon spirocycles. The reaction products can be readily transformed into sophisticated multicyclic molecules and chiral ligands.

Carbene-catalyzed enantioselective oxidative coupling of enals and di(hetero)arylmethanes.

Di(hetero)arylmethane is a unique structural motif for natural and synthetic functional molecules. To date, it remains challenging to functionalize the diaryl methyl sp3 carbon-hydrogen bond directly in an enantioselective manner. This is likely due to the relatively inert nature of the carbon-hydrogen bond and the difficult enantiofacial discrimination of two sterically similar aryl substituents. Here we disclose an N-heterocyclic carbene-catalyzed direct oxidative coupling of enals and di(hetero)arylmethanes. Our method allows for highly enantioselective transformation of diaryl methanes and quick access to benzimidazole fused lactams.

Design, synthesis and biological evaluation of novel mansonone E derivatives prepared via CuAAC click chemistry as topoisomerase II inhibitors.

Two series of novel C-9 chloro- and bromo-substituted mansonone E derivatives with triazole moieties at the C-3 position were prepared by using copper-catalysed azide-alkyne cycloaddition click chemistry. These compounds were found as potent inhibitors of topoisomerase II (Topo II) and topoisomerase I (Topo I). The Topo II-mediated pBR322 DNA relaxation and cleavage assay showed that the derivatives might act as catalytic inhibitors. Their cytotoxic activities against A549, HL-60, K562 and HeLa cells were evaluated, indicating that these compounds were potent antitumour agents. Their structure activity relationships and molecular docking study revealed that the substituents of the triazole were particularly important for cytotoxicity.

Synthesis and biological evaluation of benzo[a]phenazine derivatives as a dual inhibitor of topoisomerase I and II.

Topoisomerases (Topo I and Topo II) are very important players in DNA replication, repair, and transcription, and are a promising class of antitumor target. In present study, a series of benzo[a]phenazine derivatives with alkylamino side chains at C-5 were designed, synthesized, and their biological activities were evaluated. Most of derivatives showed good antiproliferative activity with a range of IC50 values of 1-10 µM on the four cancer cell lines HeLa, A549, MCF-7, and HL-60. Topoisomerase-mediated DNA relaxation assay results showed that derivatives could effectively inhibit the activity of both Topo I and Topo II, and the structure-activity relationship studies indicated the importance of introducing an alkylamino side chain. Further mechanism studies revealed that the compounds could stabilize the Topo I-DNA cleavage complexes and inhibit the ATPase activity of hTopo II, indicating that they are a rare class of dual topoisomerase inhibitors by acting as Topo I poisons and Topo II catalytic inhibitors. Moreover, flow cytometric analysis and caspase-3/7 activation assay showed that this class of compounds could induce apoptosis of HL-60 cells.