Insights Toward Transition-Metal-Catalyzed Csp-Csp Coupling Reaction Inspired By Kinetic Studies

As we know, the kinetic investigation plays a important role in chemical research. With the help of kinetic investigation, we can understand the reaction mechanism and the reaction process. Nowadays, kinetic studies not only confined to the understanding of the reaction mechanism, but also to guide the methodology research. This paper focuses on rational design of Pd-catalyzed Csp-Csp cross-coupling reaction inspired by kinetic studies.Due to the unique chemical and physical properties and wide applications in the pharmaceutical and material area, diynes have attracted scientists’attention for decades. However, the syntheses of diynes still remain a great challenge. Especially, compared with the intensively developed biaryl and arylalkynes syntheses (the Csp2-Csp2and Csp2-Csp couplings), the methods for Csp-Csp coupling reactions are rare, and lack high efficiency for most of the cases. Recently, the ligand-free Pd(OAc)2catalytic system was extensively studied, in which Pd-nanoparticles [Pd(NPs)] was proposed to be the active catalytic species.From kinetic investigation, an efficient Pd-catalyzed highly selective Csp-Csp cross-coupling reaction between terminal alkynes and1-bromoacetylenes has been demonstrated. With low catalyst loading (only0.0001mol%to0.01mol%of Pd is required), high selectivity and good to excellent yields could be achieved. Preliminary kinetic studies indicated that this transformation might involve PdNPs species. The TON of the reaction could reach up to350000by using this highly active Pd-catalyst. From the synthetic point of view, this protocol represents an extremely simple and efficient way to construct unsymmetrical1,3-diynes under mild conditions.Due to a two-year experiment in the United States in2007-2009, the last Chapter is a selective introduction of what I have done abroad.Over-expression of P-glycoprotein (Pgp) in some cancer cells is a primary cause of multidrug resistance (MDR) that results in chemotherapy failure. As a consequence, Pgp has been a longsought target for drug development in the hope of circumventing MDR in clinical oncology. More than three decades of biochemical studies have indicated that Pgp might possess several distinct substrate-binding sites within a large, flexible region located between the two transmembrane domains; these sites recognize hundreds of chemically unrelated compounds, including a majority of traditional anti-cancer drugs. These compounds can be exported from cells by Pgp using energy released by self-catalyzed ATP hydrolysis in conjunction with substantial conformational changes. Our groups recently determined a structure of mouse Pgp at3.8resolution by X-ray diffraction. We also solved the cocrystal structures of Pgp with a pair of enantiomeric cyclic peptides, Se-RRR and Se-SSS, in which the two enantiomers bind to Pgp with different stoichiometries and at distinct sites within a transmembrane portal open to the cytoplasmic side. These structures provided the first glimpse of the polyspecific drug-binding site of Pgp in atomic detail...