Organocatalyzed Asymmetric Synthesis Of Aza-spirooxindole Derivatives And Design, Synthesis And Bioactivities Studies Of ALK And B-Raf Inhibitors

This thesis consists of four parts:1) organocatalyzed asymmetric synthesis of3,3’-aza-spirooxindole derivatives;2) organo-and gold co-catalyzed asymmetric synthesis of3,2’-aza-spirooxindole derivatives;3) design, synthesis and bioactivities studies of novel ALK inhibitors;4) design, synthesis and bioactivities studies of novel B-Raf inhibitors.Oxindole represents an important scaffold found in natural products and biologically active compounds, such as aza-spirooxindole derivatives bearing a quaternary carbon stereocenter at C-3position have shown anticancer and antimalaria activities. Due to their special structures and propeties, asymmetric construction of spirooxindole derivatives was one of hot topics in organic chemistry. A new oxindole substrate bearing malonate ester moiety was designed in the first part. With cinchona alkaloid thiourea and benzonic acid as cooperative organocatalysts, a highly enantioselective Michael addition of2-oxindole-3-carboxylates to nitroolefins had been achieved. This catalytic system displayed broad substrate scope and gave the corresponding25adducts in91-99%yields with72-98%ee. Moreover, the final compounds could be transferred to3,3’-aza-spirooxindole and CPC-1derivatives with high enatioselectivity.The second part:a novel highly efficient one-pot sequivuential organo-and gold-catalyzed Mannich and hydroamination reaction of N-Boc-protected oxindole imine to progargylated malononitrile had been designed and developed. After optimization of organic catalyst in the first Mannich reaction step, gold catalyst in the second hydroamination step and sequivuential reaction condition,15spirooxindole derivatives had been obtained in56-91%yield,64-97%ee and more than20:1exo/endo selecivity.Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase and member of the insulin receptor super family. ALK is expressed as part of aberrant fusion proteins in a number of cancers including anaplastic large-cell lymphomas (ALCL), non-small cell lung cancer (NSCLC), inflammatory myofi-broblastic tumors (IMT) and a variety of solid tumor types. Our research efforts had focused on developing potent and selective inhibitors of ALK with modification of NVP-TAE684, including three major regions of the molecule designated as the head group, hydrophilic and core regions. Finally, total70new compounds had been designed and obtained and26compounds showed more than50%inhibition at1μM against ALK enzyme. Two final compounds A5and A15displayed the best potency (IC50=81.8nM and91.5nM). B-Raf is a serine/threonine specific protein kinase and a component of the ERK/MAPK cell signaling pathway. B-Raf is also a human oncogene that is mutated in approximately50%of malignant melanomas and at a lower frequivuency in other human cancers. A series of novel selective against B-Rafv600E inhibitors had been discovered based on virtual screening strategy. Total25novel compounds had been designed, synthesized and activity tested. Compound B24exhibited submicromolar activity against BRAFV600E (IC50=0.63μM).